KR20070011594A - New piperazine derivatives of dialkyl oxindoles - Google Patents

Abstract

The present invention is concerned with new 3,3-disubstituted indol-2-one derivatives of general formula (I), which are useful in the treatment of prophylaxis of diseases of the central nervous system, the gastrointestinal system and the cardiovascular system. ® KIPO & WIPO 2007

Description

Piperazine derivatives of dialkyl oxindoles {NEW PIPERAZINE DERIVATIVES OF DIALKYL OXINDOLES}

The present invention relates to novel 3,3-disubstituted indole-2-one derivatives, methods for their preparation, pharmaceutical compositions containing said fresh indole-2-one derivatives and the use of said compounds for the treatment of diseases.

More specifically, the present invention relates to novel 3,3-disubstituted indole-2-one derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof:

Wherein R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s);

R ² is hydrogen or halogen;

R ³ is hydrogen, alkyl with 1 to 7 carbon atom (s) with or without aryl substituents or aryl with or without one or two halogen substituent (s);

R ⁴ is alkyl having 1 to 7 carbon atom (s);

R ⁵ is a group of formula (IIa) or (IIb),

Wherein Q and W are each nitrogen or CH;

R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen, trifluoromethyl, alkyl or alkoxy having 1 to 7 carbon atom (s), or

R ⁶ and R ⁷ together represent ethylenedioxy;

m is 0, 1 or 2;

a is a single, double or triple bond;

n is 0, 1 or 2.

US Patent 4,452,808 discloses 4-aminoalkyl indol-2-one derivatives with selective D ₂ receptor activity. These compounds can be used to treat hypertension. Dolon, 4- [2- (di-N-propylamino) ethyl] -2 (3H) -in, one of the compounds set forth in this patent, is used in the clinical treatment of Parkinson's disease.

EP 281,309 discloses indole-2-one derivatives having an arylpiperazinyl-alkyl substituent at the 5 position, which can be used for the treatment of psychotic diseases. One of the compounds described in this patent is 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -ethyl] -6-chloro-1,3- Dihydro-2H-indol-2-one is D ₂ , 5-HT _1A and It is active by interaction with the 5-HT ₂ receptor and is used in clinical treatment as an antipsychotic.

EP 376,607 discloses indole-2-one derivatives substituted at the 3-position by alkylpiperazinyl-aryl groups, which are active against the 5-HT _1A receptor, useful for the treatment of central neurological diseases.

International patent application WO 98/008816 discloses indole-2-one derivatives with alkyl-piperazinyl, substituted alkyl-piperidinyl or alkyl-cyclohexyl groups substituted in the 3-position. These compounds are psychotropic.

The acceleration of social science development in the twentieth century continues to put pressure on human adaptation, which can lead to the inadvertent occurrence of compliance disorders. Adaptation disorders are important risk factors for the development of diseases of mental or mental-body origin, such as anxiety syndrome, stress diseases, depression, schizophrenia, diseases of the sensory organs, gastrointestinal tract diseases, cardiovascular disease, kidney disease.

For the treatment of this clinical pattern, the widest range of agents used was active against the benzodiazepine system (eg diazepam) or against the central 5-HT _1A receptor (eg buspyrone, ziprasidone). In the case of psychosomatic diseases, treatment for anxiety is often complemented by the administration of a medicament with antihypertensive activity (acting on α ₁ or α ₂ receptor), or gastric ulcer inhibitory activity (H ₁ -receptor antagonist).

However, benzodiazepine type anti-anxiety agents have several unpleasant side effects. These anti-anxiety agents have a strong calming activity resulting in a decline in concentration and memory, and have a muscle relaxation effect. These side effects affect the quality of life of the patient in an unintended way, thus limiting the scope of application of these drugs.

However, agents acting on the 5-HT _1A receptor, which have been used for treatment until now, have serious disadvantages and undesirable side effects. The disadvantage is that the anxiety relief effect can only be achieved after continuing treatment for 10 to 14 days or more. In addition, anxiogenic effects develop after the initial administration. As a side effect, the occurrence of drowsiness, sleepiness, dizziness, hallucinations, headaches, cognitive impairment or vomiting is often observed. This effect of the drug makes cooperation between the doctor and the patient more difficult because the patient believes that exacerbation of these symptoms is the result of drug administration.

In addition to the stresses of adapting to the environment, another major problem in modern society is the accelerated population aging. As a result of modern medical science, life expectancy has increased, and the disease caused by aging, particularly many mental illnesses, is rapidly increasing. Therapeutic solutions for Alzheimer's disease, vascular dementia, and senile dementia are emerging as social problems.

Another consequence of the aging process is a significant increase in the number of deaf people. According to the WHO statistics, as of 2001, 250 million people suffer from moderate to severe hearing dysfunction. Geriatric hearing impairment may occur in 10% and 25% of the population of 45-55 and 65-75 years, respectively.

As listed above, there is an urgent need for new and efficient drugs that are more effective against the disease than those currently used.

Summary of the Invention

It is an object of the present invention to avoid the above-mentioned disadvantages and undesirable side effects of active agents that bind to the 5-HT _1A receptor, while at the same time developing pharmaceutical components that can be used for the treatment of central nervous system diseases.

The present invention provides that the 3,3-dialkyl-substituted indole-2-one derivatives of formula (I) possess a significant anxiolytic effect and surprisingly bind to the 5-HT _1A receptor in contrast to prior art compounds of similar structure. Based on the amazing perception of not doing As a preferred result, the compounds according to the invention avoid the above-specified side effects of compounds which bind to said receptors. In addition, surprisingly, the compounds of formula (I) according to the invention also bind to 5-HT _2C and α ₁ receptors, the activity of which leads to dopamine release, which significantly extends the scope of therapeutic applications.

According to one aspect of the invention, R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s);

R ² is hydrogen or halogen;

R ³ is hydrogen, alkyl having 1 to 7 carbon atom (s) with or without aryl substituents or aryl with or without one or two halogen substituent (s);

R ⁴ is alkyl having 1 to 7 carbon atom (s);

R ⁵ is a group of formula (IIa) or (IIb),

Wherein Q and W are each nitrogen or CH;

R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen, trifluoromethyl, alkyl or alkoxy having 1 to 7 carbon atom (s), or

R ⁶ and R ⁷ together represent ethylenedioxy;

m is 0, 1 or 2;

a is a single, double or triple bond;

Provided are novel 3,3-disubstituted indol-2-one derivatives of formula (I) wherein n is 0, 1 or 2 and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 7, preferably 1 to 4 carbon atom (s) (eg, methyl, ethyl, 1 -Propyl, 2-propyl, n-butyl, isobutyl or tert-butyl groups and the like).

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms, preferably chlorine or bromine.

Leaving groups are alkylsulfonyloxy or arylsulfonyloxy groups such as methylsulfonyloxy (mesyloxy) or p-toluenesulfonyloxy groups; Halogen atoms, preferably bromine or chlorine.

The term "pharmaceutically acceptable acid addition salt" denotes a nontoxic salt of a compound of formula (I) formed with a pharmaceutically acceptable organic or inorganic acid. Inorganic acids suitable for salt formation are, for example, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid or nitric acid. As the organic acid, formic acid, acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, malonic acid, oxalic acid, mandelic acid, glycolic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Naphthalic acid or methanesulfonic acid can be used. In addition, carbonates and hydrocarbon salts are also considered pharmaceutically acceptable salts.

Preferred groups of compounds of formula (I) possessing valuable pharmaceutical properties include R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s); R ² is hydrogen or halogen; R ³ is hydrogen; R ⁴ is ethyl- or 2-methylpropyl; R ⁵ is a group of formula (IIa) or (IIb), wherein Q is nitrogen and W is a CH group; R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen or alkoxy having 1 to 7 carbon atom (s), or R ⁶ and R ⁷ together form an ethylenedioxy group; m is 0 or 1; a is a single bond; n is 1 and a pharmaceutically acceptable acid addition salt of the compound of formula (I).

Preferred groups of compounds of formula (I) possessing valuable pharmaceutical properties include R ¹ is hydrogen or halogen; R ² is hydrogen or halogen; R ³ is hydrogen; R ⁴ is ethyl; R ⁵ is a group of formula (IIa); R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen or alkoxy having 1 to 7 carbon atom (s); m is 1; a is a single bond; n is a 0 or 1 derivative and a pharmaceutically acceptable acid addition salt of the compound of formula (I).

Another group of compounds of formula (I) possessing particularly preferred activities are R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s); R ² is hydrogen; R ³ is hydrogen; R ⁴ is ethyl- or 2-methylpropyl; R ⁵ is a group of formula (IIa); R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen or alkoxy having 1 to 7 carbon atom (s), or R ⁶ and R ⁷ together form an ethylenedioxy group; m is 1; a is a single bond; n includes a derivative of 1 and a pharmaceutically acceptable acid addition salt thereof.

According to a further aspect of the present invention there is provided a process for preparing a compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof,

(a) reacting a compound of formula (III) with a piperazine derivative of formula (IV) in the presence of an acid binder,

(b) reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a strong base, or

(c) To prepare a compound of formula (I) wherein n is 1 and a is a triple bond, the compound of formula (VIII) is reacted with formaldehyde, and thus the compound of formula (III) wherein L is a hydroxy group Is optionally converted to a compound of formula (III) wherein L is a halogen atom or an arylsulfonyloxy or alkylsulfonyloxy group, and thus a compound of formula (III) wherein a is a triple bond and n is 1 is in the presence of a strong base React with a compound of formula (IV)

(d) to prepare a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as mentioned above and a is a single or double bond, a is a triple bond Reducing the corresponding compound of formula (I)

(e) To prepare a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as mentioned above and a is a single bond, a is a double or triple bond Reducing the corresponding compound of formula (I)

If desired, there is provided a method comprising halogenating a product containing hydrogen at the position of R ² , releasing the free base from its salt or converting it to an acid addition salt with a pharmaceutically acceptable organic or inorganic acid. do:

Wherein L is a leaving group, preferably chlorine or bromine,

m and n are each 0, 1 or 2,

a is a single, double or triple bond,

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as mentioned above.

Compounds of formula (I) wherein R ¹ -R ⁵ , a, m and n are mentioned above, are compounds of formula (III) wherein R ¹ -R ⁴ , a, m and n are Wherein L is a leaving group, and the compound of formula (IV) wherein R ⁵ is as mentioned above and Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, ed. 4, vol. E16d (ed .: D. Klamann); RC Larock: Comprehensive Organic Transformations, ed. 2, John Wiley & Sons, New York, 1999, 789; DA Walsh, YH. Chen, JB Green, JC Nolan, JM Yanni J. Med. Chem. 1990, 33, 1823-1827, which may be prepared by reacting according to methods analogous to those known from 1990, 33, 1823-1827.

During the preparation of the compounds of formula (III), the formation of substituents can be carried out optionally proceeding according to methods known in the literature. It is easy to prepare a compound of formula (III) by reacting a compound of formula (V) with a compound of formula (VI), wherein R ¹ -R ⁴ are as mentioned above, which is described in Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, ed. 4, vol. V / 2b; AR Katritzky, Ch. W. Rees: Comprehensive Hetero-cyclic Chemistry, ed. 1, Pergamon, Oxford, 1984, vol. 4. (ed .: CW Bird, GWH Cheeseman), 98-150 and 339-366; GM Karp Org. Prep. Proc. Int. 1993, 25, 481-513; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597, is constructed according to the method known:

Wherein L, a, m and n are as mentioned above and L 'is a leaving group or a group which can be converted to a leaving group.

R ¹ -R ⁵ , a. Compounds of formula (I) in which m and n are mentioned above include compounds of formula (VI), wherein R ¹ -R ⁴ are as mentioned above; compounds of formula (VII), wherein R ⁵ , a, m and n are as mentioned above, L is a leaving group) and RJ Sundberg: The chemistry of indoles, Academic Press, New York, 1970, chapter VII .; AR Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1 ^th Edition, Pergamon, Oxford, 1984, vol. 4 (ed .: CW Bird, GWH Cheeseman), 98-150 and 339-366; GM Karp Org. Prep. Proc. Int. 1993, 25, 481-513; AS Kende, JC Hodges Synth. Commun. 1982, 12, 1-10; WW Wilkerson, AA Kergaye, SW Tam J. Med. Chem. 1993, 36, 2899-2907 , which may be prepared by reacting according to methods known in the art.

Compounds of formula (I) wherein R ¹ -R ⁵ and m are as mentioned above, a is a triple bond and n is 1 are compounds of formula (VIII), wherein R ¹ -R ⁴ and m are As mentioned above, compounds of formula IV in which R ⁵ is as mentioned above and Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4 ^th Edition, vol. V / 2a (ed .: E. Muller), 545-549; BM Trost, I. Fleming: Comprehensive Organic Syntheses, 1 ^th Edition, Pergamon Press, Oxford, 1991, vol. 2 (ed .: CH Heathcock), 893-898; K ishizumi, A. Kojima, F. Antoku Chem. Pharm. Bull . 1991, 39 , 2288-2300, can also be prepared by the reaction according to the method known in the art.

In certain cases, the reaction may also be carried out in several stages, i.e. in the first stage reaction of a compound of formula (VIII), wherein R ¹ -R ⁴ and m are as mentioned above with formaldehyde To give a compound of formula III wherein R ¹ -R ⁴ and m are as mentioned above, n is 1, a is a triple bond and L is hydroxy. The compound thus obtained is then directly reacted with a compound of formula (IV) or the L = OH group is first converted to a more suitable leaving group by a method known in the literature and then reacted with a compound of formula (IV) to form To yield a compound of which R ¹ -R ⁵ and m are as mentioned above, a is a triple bond and n is 1.

Compounds of formula (I) wherein R ¹ -R ⁵ , m and n are as mentioned above, a is a single or double bond, and R ¹ -R ⁵ , m and n are as mentioned above, and a is a triple bond Phosphorus compounds of formula (I) are described in Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1980, 4th Edition, vol. IV / lc and IV / ld (ed .: H. Kropf); J. March: Advanced Organic Chemistry, Reactions, mechanisms and structures, 4 ^th Edition, John Wiley & Sons, New York, 1992, 771-780, can also be prepared by reduction.

Compounds of formula (I) wherein R ¹ -R ⁵ , m and n are as mentioned above and a is a single bond, and R ¹ -R ⁵ , m and n are as mentioned above and a is a double bond Compounds of (I) are described in Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1980, 4th Edition, vol. IV / lc and IV / ld (ed .: H. Kropf); J. March: Advanced Organic Chemistry, Reactions, mechanisms and structures, 4 ^th Edition, John Wiley & Sons, New York, 1992, 771-780, can also be prepared by reduction.

Compounds of formula (I), in which R ¹ -R ⁵ , a, m and n are mentioned above, can be prepared by successive succession in the last reaction step to form the substituents R ¹ -R ⁸ . In this case, compounds of formula (I) are used as starting materials and all substituents except the one formed are as mentioned above. Introduction and conversion of substituents are described in Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4 ^th Edition, IV / la-d; vol. V / 2b]. It may be necessary to apply or remove protecting groups during the introduction of substituents. This method is specified in TW Greene, Protective groups in organic synthesis, John Wiley & Sons, 1981.

Compounds of formula (IV), (V) and (VII) are known in the literature or can be prepared by analogous methods.

Compounds of formula (VI) wherein R ¹ -R ⁴ are mentioned above can be prepared by known methods, and the formation of substituents is described in AR Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1 ^th Edition Pergamon, Oxford, 1984, vol. 4 (ed .: CW Bird, GWH Cheeseman), 98-150 and 339-366; C. Gautier, M. Aletru, Ph. Bovy WO 99/62900; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597; GM Karp Org. Prep. Proc. Int . 1993, 25, 481-513; AS Kende, JC Hodges Synth. Commun . 1982, 12, 1-10, and optionally proceeds according to methods known in the art.

During the preparation of compounds of formula (VIII) wherein R ¹ -R ⁴ are as mentioned above and m is 1, 2 or 3, the introduction of the substituents R ¹ -R ⁴ and-(CH ₂ ) _m -C≡CH AR Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1 ^th Edition, Pergamon, Oxford, 1984, vol. 4 (ed .: CW Bird, GWH. Cheeseman), 98-150 and 339-366; C. Gautier, M. Aletru, Ph. Bovy WO 99/62900; B. Volk, T. Mezei, Gy. Simig Synthesis 2002,595- 597; GM Karp Org. Prep. Proc. Int. 1993, 25, 481-513; AS Kende, JC Hodges Synth. Commun . 1982, 12 , 1-10 may be optionally carried out according to the method known. Compounds of formula (VIII) are those of formula (IX) wherein m is 1, 2 or 3 and L is a leaving group, according to methods known in the literature, wherein R ¹ -R ⁴ are compounds of formula (VI) as mentioned above It is preferred to be prepared by alkylation with a compound.

Compounds of formula (I) prepared according to the invention can be converted from these salts into free or pharmaceutically acceptable acid addition salts by methods known from the literature.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising as an active ingredient a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with one or more conventional carrier (s) or adjuvant (s). do.

Pharmaceutical compositions according to the invention generally contain 0.1 to 95% by weight, preferably 1 to 50% by weight, in particular 5 to 30% by weight of the active ingredient.

Pharmaceutical compositions of the invention may be administered orally (eg, powders, tablets, coated tablets, capsules, microcapsules, pills, solutions, suspensions or emulsions), parenteral administration (eg, intravenous, intramuscular, subcutaneous or Infusions for intraperitoneal use), rectal administration (eg suppositories), transdermal administration (eg bandages) or topical administration (eg ointment or bandages) or in the form of implants. May be suitable. Solid, soft or liquid pharmaceutical compositions according to the invention can be prepared by methods commonly used in the pharmaceutical industry.

Solid pharmaceutical compositions for oral administration containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof include fillers or carriers (e.g., lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binders (e.g., , Gelatin, sorbite, polyvinyl pyrrolidone), disintegrants (e.g. croscarmellose, Na-carboxy-methyl cellulose, crospovidone), tableting aids (e.g. magnesium stearate, talc, polyethylene glycol, silicic acid, dioxide) Silicon) and surfactants (eg, sodium lauryl sulfate).

Liquid compositions suitable for oral administration may be solutions, suspensions or emulsions. Such compositions include suspending agents (eg gelatin, carboxymethyl cellulose), emulsifiers (eg sorbitan monooleate), solvents (eg water, oil, glycerol, propylene glycol, ethanol), buffers (eg acetate, phosphate) , Citrate buffer) and preservatives (eg, methyl-4-hydroxybenzoate).

Liquid pharmaceutical compositions suitable for parenteral administration are generally sterile isotonic solutions, optionally containing buffers and preservatives in addition to solvents.

Soft pharmaceutical compositions, such as suppositories, containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as the active ingredient, the active ingredient uniformly dispersed in suppository base materials (e.g., polyethylene glycol or coconut butter) It contains.

According to a further aspect of the invention, anxiety syndromes, in particular generalized anxiety disorders, panic disorders, obsessive compulsive disorder, social phobia, agoraphobia, phobias associated with specific situations, post-traumatic stress disorder, post-traumatic memory disorders, cognitive impairment, central Indole-2-one of formula (I) for the manufacture of a pharmaceutical composition suitable for the treatment or prevention of central nervous system diseases or psychosomatic diseases, including sexual dysfunction, depression, schizophrenia, gastrointestinal diseases, and cardiovascular diseases of nervous system origin. The use of a derivative or a pharmaceutically acceptable acid addition salt thereof is provided.

Pharmaceutical compositions according to the invention can be prepared by methods known in the pharmaceutical industry. The active ingredient is mixed with a pharmaceutically acceptable solid or liquid carrier and / or adjuvant, which mixture is in the form of a herbal. Such carriers and auxiliaries, along with methods that can be used in the pharmaceutical industry, are disclosed in Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990.

Pharmaceutical compositions according to the invention generally contain a unit dose. The daily dose of an adult may generally be from 0.1 to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof per kg body weight. Such daily doses may be administered in one or more portion (s). In fact, the daily dose depends on several factors and is determined by the physician.

According to a further aspect of the invention, anxiety syndromes, in particular generalized anxiety disorders, panic disorders, obsessive compulsive disorder, social phobia, agoraphobia, phobias associated with certain situations, stress disorders, post-traumatic stress disorders, post-traumatic memory disorders, cognition Disorders, sexual dysfunction of central nervous system origin, depression, schizophrenia, mental decline due to cerebral cell death, Alzheimer's disease, stroke, dementia, and also gastrointestinal diseases, and central nervous system diseases including cardiovascular diseases, especially hypertension and psychosomatic diseases For the treatment or prophylaxis there is provided the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. The mixtures according to the invention can also be used to treat disorders of the hearing organ, tinnitus, which appear as a result of treatment regimens.

Compounds of the 1,3-dihydro-2H-indol-2-one type of the prior art bind in a selective manner to the 5-HT _1A receptor, affecting the central nervous system, see European Patent Specification 376.607 and the technical literature [ A. Dekeyne, JM Rivet, A. Gobert, MJ Millan: Neuropharmacology 40 (7) p. 899-910 (2001); JS: Sprouse et al .: Neuropsycho-pharmacology 21 (5) p. 622-631 (1999); A. Newman-Tancredi et al .: Eur. J. Pharmacol. 355 (2-3) pp. 245-246 (1998). Thus, they are used as anxiolytics and can be used to treat depression, as well as cardiovascular, gastrointestinal and kidney diseases.

The present invention is based on the surprising recognition that the 3,3-dialkyl indol-2-one derivatives of formula (I) possess anxiolytic activity but do not bind to the 5-HT _1A receptor. In other words, this is why the compounds according to the invention can be expected to avoid the aforementioned side effects which are characteristic of the active ingredient binding to the 5-HT _1A receptor. Another surprising recognition is that compounds of formula (I) affect dopamine release in the ear and bind to the α ₁ receptor, in addition to the anxiety alleviating activity that may result in connection with binding to the 5-HT _2C receptor.

Receptor binding, except for 5-HT _2C receptor binding, was measured using cerebral region preparations of male Wistar rats weighing 120-200 g. 5-HT _1A receptor binding frontal cortex preparations were used for the preparation. α ₁ receptor binding studies were performed from isolated frontal cortex preparations. Porcine chorus froze was used for 5-HT _2C receptor binding experiments. The protein content of the membrane preparations was measured by the method of Lowry (1951).

5-HT _1A receptor binding was performed by Peroutka [Peroutka, SJ: J. Neurochem. 47, p. 529 (1986)]. The ligand was tritiated 8-hydroxy-N, N-dipropyl-2-aminotetraline (8-OH-DPAT). 10 μM serotonin was used for the measurement of nonspecific binding. Incubation blood volume was 250 μl. Incubation was performed for 30 minutes at room temperature of 25 ° C. The reaction was terminated by addition of 9 ml ice cold 50 mM TRIS-HCl (pH 7.7) buffer and rapid vacuum filtration using Whatman GFIB fiberglass filter paper. Radioactivity of the filter board was measured by liquid scintillation spectrophotometer.

In the 5-HT _2C and α ₁ receptor binding experiments, the ligands were ³ H-mesulergin (1.0 nM) and ³ H-prazosin (0.3 nM), respectively. Nonspecific binding ligands were mianserine (1 μM) and prazosin (1 μM), respectively.

IC ₅₀ is a value at a concentration where the difference between total and nonspecific binding is 50% in the presence of a certain concentration of specific ligand. Compounds with IC ₅₀ values of less than 100 nmol are considered effective in this test. The experimental results are shown in Tables 1-3.

Table 1: 5-HT _1A Receptor Binding

From the results in Table 1, it can be seen that the test compound does not bind to the 5-HT _1A receptor.

Table 2: 5-HT _2C Receptor Binding

Table 3: α ₁ Receptor Binding Experiments

As demonstrated from Tables 2 and 3, the compounds according to the invention show significant binding to the 5-HT _2C and α ₁ receptors.

The anxiety alleviating effect according to the present invention was investigated in the drinking conflict test and elevated plus-maze test of Pogel [S. Pelow, P. Chopin, S.E. File, J. Briley: Neurosci. Methods 14, p. 149 (1985)].

Vogel's drinking conflic test

Male Wistar rats weighing 160-180 g were used for the experiment. Prior to testing, animals were given 24 hours of fasting without drinking water for 48 hours. Test compounds or vehicles were administered intraperitoneally 30 minutes prior to testing. In the test chamber, animals had free access to drinking water. An electric shock (0.7 mA) was applied through the beverage drain after every 20 licks during the 5 minute test period. The number of corporal punishment licks was recorded. The effect of the test compound is expressed as an increase in the number of times the shock is tolerated. Minimum effective dose (MED) was determined for each compound. The results are shown in Table 4 below.

Table 4: Drinking Conflict Test of Pogel

Elevated Plus-Maze Examination in Rats

A wooden cross rising 50 cm above the floor and 15 cm wide with a 100 cm long sleeve was used for the experiment. The sides and ends of the two opposite arms of the cross were installed on a 40 cm high wall, and the arms were opened to a 15 cm x 15 cm central zone (closed arm). Two different arms were not enclosed by the wall (open arms).

200-220 g male Sprague-Dawley rats were used for the experiment. The animals were placed in the central area of the device and after 60 minutes of treatment the following four parameters were observed for a 5 minute test time:

Time spent in open arms in seconds,

Time spent in closed arms in seconds,

Number of entries in open arms,

Number of entries in closed arms.

The effect was expressed as the percentage of time spent in the open arm or the number of entries into the open arm. MED (minimum effective dose) was measured for each compound. The results are summarized in Table 5 below.

Table 5: Elevated Plus-Maze in Rats

From the data in the table, it can be seen that the compound of formula (I) possesses a significant anxiolytic effect.

A study of the effects on hearing impairment and tinnitus is described by Gaborjan et al. (Gaborjan, A., Lendvai, B, Vizi, E.S .: Neuroscience 90, p. 131 (1999)] in guinea pigs (Toxicoop, Hungary) weighing 145 to 375 g. Dopamine release in the inner ear as a result of hearing impairment was measured using high pressure liquid chromatography (HPLC) in samples from the snail preparation (outer olive snail neural nerve). Samples were collected every 3 minutes for 60 minutes (20 fractions). Electric field stimulation was generally applied during the 3rd and 13th fractions (S1, S2, 2Hz, 360 shock, 60V; Grass Medical Instruments). In each experiment, ischemia (oxygen and glucose deprivation, OGD) was mimicked by perfusion of a buffer saturated with 100% N2 and containing saccharose instead of glucose. The results are expressed as percent dopamine release per perfusion. Statistical analysis was performed by analysis of variance (ANOVA) followed by Tukey test.

From the results thus obtained, the effect of Example 76 compound on dopamine release in the inner ear of guinea pig is shown (FIG. 1). Early stimulation (SI) caused significant dopamine release. This release is reduced after the second stimulus following oxygen and glucose deprivation, but in the presence of the Example 76 compound, the release was stabilized at a much higher level than in the absence of oxygen and glucose deprivation. This effect can be interpreted as suppression of hearing damage.

The neuroprotective effect of the compounds according to the invention has been demonstrated in a global cerebral ischemia model induced by both carotid artery occlusions. Male Mongolian gerbilus rats weighing 60-90 g were used as test animals. Test compounds were administered intraperitoneally at a dose of 30 mg / kg 45 minutes after surgery. The test material was suspended in 0.4% methyl-cellulose solution. Under diethyl ether anesthesia, the right and left condylar arteries were exposed through anterior central uterine incision and separated from the vagus nerve and surrounding tissue. A complete stop of the carotid artery blood flow was achieved by tightening the aneurysm clip for 3 minutes. During surgery, the body temperature of the animal was maintained at the preoperative level of the subject (37.5 ± 0.5 ° C.) with the help of a heating pad and a heating lamp.

On day 4 post-op, animals are anesthetized with 60 mg / kg of nembutal (ip) (10 ml / kg), first with saline followed by 0.1% glutaraldehyde, 4% paraform in 0.1 M phosphate buffer (pH 7.4). Perfusion through the heart for 30 minutes with a fixed solution containing aldehyde and 0.2% picric acid. The brain was removed from the skull and postfixed at 4 ° C. for at least 1 week in the same fixation solution.

Alternate tubular sections of 60 μm thickness were cut from different levels of the dorsal hippocampus by microtome. Sections were washed repeatedly with 0.1 M phosphate buffer and then stained by silver infiltration. Sections are stored twice in a preliminary solution (2% sodium hydroxide and 0.875% ammonium hydroxide solution) for 5 minutes, injected into the 0.875% ammonium hydroxide solution and 0.5% silver nitrate solution for 10 minutes and dissolved in a wash solution (29.1% aqueous ethanol solution). 0.5% sodium carbonate and 0.01% ammonium nitrate) twice for 2 minutes and once for 1 minute. The slices were then formulated in a 9.9% ethanol solution containing 1.5% formaldehyde and 0.1% ammonium nitrate and fixed in 0.5% acetic acid solution three times for 3 minutes. Stained slices were placed in 0.1 M phosphate buffer (pH 7.4) and chromium gelatin, applied onto plates, dehydrated and treated with xylol. The cover plate was fixed with DPX adhesive (Fluka).

Sections were examined under light microscopy and scored at 6 points on the total neuronal damage in hippocampal CA1 subpopulations of both hippocampus: (0) intact, (1) -0-10%, (2) -10-30 %, (3) -30-50%, (4) -50-70%, (5) -70-90% and (6) -90-100% cell loss. Differences between drug-treated and vehicle-treated groups were statistically analyzed by the Mann-Whitney U-test. The results are summarized in Table 6.

Table 6: Neuroprotective effects in the overall ischemic test

The experimental results demonstrate that the compounds according to the invention significantly reduce the rate of cell death in the CA1 region of the animal hippocampus recovered from overall cerebral ischemia. The results demonstrate that the test compound possesses significant neuroprotective activity.

Based on the above experiments, it can be proved that the novel compounds according to the invention are effective for the treatment of certain diseases of the central nervous system and the cardiovascular system. These central nervous system diseases include different forms of anxiety (generalized anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, social phobia, depression, mental decline due to cerebral cell death (eg Alzheimer's disease, stroke, dementia) In addition, the compounds according to the invention are suitable for the treatment of cardiovascular diseases, in particular hypertension The compounds according to the invention are further effective in hearing impairment and tinnitus which appear as side effects of medical treatment.

Surprisingly, the compounds according to the invention do not act on the 5-TH _1A receptor in contrast to the compounds of the prior art of similar structure. They bind well to the 5-HT _2C receptor, which is believed to play a role in the pathogenesis of anxiety. The α ₁ receptive effect of the compounds according to the invention suggests that they can be used for the treatment of cardiovascular diseases. Dopamine releasing activity in the inner ear of guinea pigs indicates that they are useful for the treatment of hearing impairment and tinnitus.

More details of the invention are described in the following examples, but the scope of protection should not be limited to the examples.

Example 1

5-chloro-3-ethyl-1,3-dihydro-2H-indol-2-one

See, B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595 to give the title compound from 5-chloro-oxindole. 1.68 g (0.01 mole) of 5-chloro-oxindole was dissolved in 20 ml of ethanol and 1.0 g of Raney-nickel was added to the solution. The mixture was reacted for 36 h at 110 ° C. in an autoclave. The catalyst was then filtered off, the solvent was evaporated and the residue was recrystallized from a mixture of hexane and ethyl acetate. Yield: 0.86 g of white powder (44%).

M.p .: 121-123 ° C. (hexane-ethyl acetate).

IR (KBr): 3156, 1701 (C = O), 782 cm ^-1 .

¹ H-NMR (CDCl ₃ ): 9.27 (br s, 1H, NH), 7.21 (lH, s, H-4), 7.19 (d, 1H, J = 8.8 Hz, H-6), 6.85 (d, 1H, J = 8.1 Hz, H-7), 3.47 (t, 1H, J = 5.5 Hz, H-3), 2.03 (m, 2H, CH ₂ ), 0.92 (t, 3H, J = 7.0 Hz, CH ₃ ) ppm.

¹² C-NMR (CDCl ₃ ): 180.5, 140.4, 131.2, 127.8, 127.6, 124.5, 110.7, 47.5, 23.5, 9.9 ppm.

Anal for Formula C ₁₀ H ₁₀ ClNO (195.65):

Calculated: C 61.39, H 5.15, N 7.16, Cl 18.12%.

Found: C 61.16, H 5.10, N 6.93, Cl 18.11%.

Example 2

5-bromo-3-ethyl-1,3-dihydro-2H indol-2-one

3-ethyl-oxindole (16.1 g; 0.10 mole) is dissolved in 350 m1 of acetonitrile, the solution is cooled to 0 ° C. and N- bromo-succinimide (17.8 g; 0.10 in 150 ml of acetonitrile) The solution of mole) was added dropwise thereto within 2 hours at the same temperature. The reaction mixture was first stirred at 0 ° C. for 1 hour and then at room temperature for 3 hours. The solution was evaporated, the white material separated in crystalline form was extracted with dichloro-methane and 1 M NaOH solution, and the organic phase was extracted again with alkaline water to remove succinimide. The organic phase was dried over sodium sulphate, filtered and evaporated. The isolated white material was recrystallized from a mixture of heptane and ethyl acetate. Yield: 15.24 g of white powder (63%).

M.p .: 125-127 ° C. (heptane-ethyl acetate).

IR (KBr): 3154, 1700 (C = O), 812 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.90 (1H, s), 7.36-7.32 (2H, m), 6.81 (1H, d, J = 8.9 Hz), 3.43 (1H, t, J = 5.8 Hz), 2.03 (2H, q, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.3, 140.8, 131.6, 130.7, 127.2, 114.9, 111.2, 47.2, 23.4, 9.9 ppm.

Analysis for Formula C ₁₀ H ₁₀ BrNO (240.10):

Calculated: C 50.03, H 4.20, N 5.83, Br 33.28%

Found: C 50.16, H 4.20, N 5.85, Br 32.70%.

Example 3

4- (4-pyrimidin-2-yl piperazin-1-yl) -but-2-yn-1-ol dihydrochloride

2- (piperazin-1-yl) -pyrimidine (10.8 g; 66 mmoles) was weighed with propargyl alcohol (3.9 ml; 66 mmoles) and copper (II) acetate monohydrate (0.75 g; 3.8 mmoles) Was added thereto and 37% aqueous formalin (20 ml, 265 mmoles) was pipetted into the reaction mixture under stirring. The green suspension was refluxed for 2 hours. It was then cooled, water and chloroform were added to it and the pale green material insoluble in both phases was filtered off. The aqueous phase was extracted twice with chloroform and the combined organic phases were dried over sodium sulphate and evaporated. The remaining brown oil was dissolved in ethyl acetate and 2 molar equivalents of hydrogen chloride solution in isopropanol was added dropwise with stirring. The separated white salt was filtered off, stirred in hot isopropanol, cooled and filtered. Yield: 12.7 g of white powder (63%).

M.p .: 187-188 ° C. (methanol).

IR (KBr): 3295, 1625 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 12.1 (br s, 1 H), 8.54 (d, J = 4.9 Hz, 2H), 7.12 (br s, 4H), 6.88 (t, J = 4.9 Hz, 1H), 4.82 (br s, 2H), 4.23 (s, 2H), 4.17 (s, 2H), 3.62-3.48 (m, 4H), 3.20 (m, 2H) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 159.1, 158.2, 111.5, 90.5, 73.1, 49.8, 49.2, 44.9, 40.9 ppm.

C ₁₂ H ₁₈ Cl ₂ N ₄ O (305.21).

Example 4

4- {4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-yn-1-ol dihydrochloride

1- (2-methoxyphenyl) -piperazine (12.7 g; 66 mmoles) was weighed with propargyl alcohol (3.9 ml; 66 mmoles) and copper (II) acetate monohydrate (0.75 g; 3.8 mmoles) was weighed. To this was added 37% aqueous formalin (20 ml, 265 mmoles) pipetted into the reaction mixture under stirring. The green suspension was refluxed for 1.5 hours. It was then cooled, water and chloroform were added to it, and a pale yellow material insoluble in both phases was filtered off. The aqueous phase was extracted twice with chloroform and the combined organic phases were dried over sodium sulphate and evaporated. The remaining brown oil was dissolved in ethyl acetate and 2 molar equivalents of hydrogen chloride solution in isopropanol was added dropwise with stirring. The separated white salt was filtered off, digested in hot isopropanol, cooled and filtered. Yield: 16.3 g white powder (74%).

M.p .: 179-181 ° C. (ethyl acetate-ethanol).

IR (KBr): 3324, 2853 cm ^-1 .

¹ H-NMR (D ₂ 0, DSS, 400 MHz): 7.45 (m, 2H), 7.25 (dd, J = 8.8, 1.2 Hz, 1H), 7.15 (dt, J = 7.7, 1.2 Hz, 1H), 4.41 (t, J = 1.7 Hz, 2H), 4.33 (t, J = 1.7 Hz, 2H), 3.99 (s, 3H), 3.85 (br s, 8H) ppm.

¹³ C-NMR (D ₂ 0, DSS, 101 MHz): 154.3, 134.6, 124.1, 122.8, 115.5, 92.4, 75.0, 58.4, 52.1, 51,7, 48.8 ppm.

C ₁₅ H ₂₂ Cl ₂ N ₂ O ₂ (333.26).

Example 5

4- [4- (3-Chlorophenyl) -piperazin-1-yl) -but-2-yn-1-ol dihydrochloride

Weigh 1- (3-chlorophenyl) -piperazine (19.7 g; 0.10 mole) with propargyl alcohol (11.8 ml; 0.20 mole), and copper (II) acetate monohydrate (1.0 g; 5.2 mmoles) here Was added and 37% aqueous formalin (50 ml) was pipetted into the reaction mixture under stirring. The green suspension was refluxed for 2 hours. It was then cooled, water and chloroform were added thereto and a pale green material insoluble in both phases was filtered off. The aqueous phase was extracted twice with chloroform and the combined organic phases were dried over sodium sulphate and evaporated. The remaining brown oil was dissolved in ethyl acetate and 2 molar equivalents of hydrogen chloride solution in ethyl acetate was added dropwise with stirring. The separated white salt was filtered off, digested with hot isopropanol, cooled and filtered. Yield: 26.6 g of white powder (79%).

M.p .: 171-173 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 8.6 (2H, br s), 7.28 (1H, t, J = 8.0 Hz), 7.07 (1H, s), 6.95 (1H, d, J = 2.0 Hz), 6.87 (1H, d, J = 2.0 Hz), 4.23 (2H, s), 4.18 (2H, s), 3.95 (2H, br s), 3.55 (2H, br s), 3.22 (4H , br s) ppm.

C ₁₄ H ₁₉ Cl ₃ N ₂ 0 (337.68).

Example 6

4- (4-phenylpiperazin-1-yl) -but-2-yn-1-ol dihydrochloride

1-phenylpiperazine (16.2 g; 0.10 mole) is weighed with propargyl alcohol (11.8 ml; 0.20 mole), and copper (II) acetate monohydrate (1.0 g; 5.2 mmoles) is added thereto, 37% Aqueous formalin (50 ml) was pipetted into the reaction mixture under stirring. The green suspension was refluxed for 2 hours. It was then cooled, water and chloroform were added thereto and a pale green material insoluble in both phases was filtered off. The aqueous phase was extracted twice with chloroform and the combined organic phases were dried over sodium sulphate and evaporated. The remaining brown oil was dissolved in ethyl acetate and 2 molar equivalents of hydrogen chloride solution in ethyl acetate was added dropwise with stirring. The separated white salt was filtered off, digested with hot isopropanol, cooled and filtered. Yield: 18.5 g white powder (61%).

M.p .: 190-193 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 7.4 (2H, broad s), 7.30 (2H, t, J = 7.3 Hz), 7.15 (2H, t, J = 8.3 Hz), 6.95 ( 1H, t, J = 7.8 Hz), 4.24 (2H, s), 4.19 (2H, s), 3.83 (2H, br s), 3.58 (2H, br s), 3.28 (2H, br s) ppm.

C ₁₄ H ₂₀ Cl ₂ N ₂ 0 (303.23).

Example 7

2- [4- (4-Chlorobut-2-ynyl) -piperazin-1-yl] -pyrimidine dihydrochloride

4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-in-1-ol dihydrochloride (9.61 g; 31.5 mmoIes) in thionyl chloride (30 ml; 0.41 mole) Was added under stirring with a spatula in small amounts. Upon completion of the addition, the reaction mixture was allowed to warm to reflux temperature. Strong gas formation can be observed, the starting material is dissolved and the product is separated in the form of a salt. 15 ml of toluene was added to the reaction mixture and stirred until gas formation stopped (about 30 minutes). The mixture was then cooled, the snow-white powder was filtered off, washed with ethyl acetate and dried. Yield: 8.77 g white powder (86%).

Mp: 178-179 ° C. (ethanol).

IR (KBr): 1622 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 12.4 (s, 1H), 8.49 (d, J = 4.9 Hz, 2H), 6.82 (t, J = 4.8 Hz, 6.7 (br s, 1H ), 4.79 (s, 2H), 4.59 (s, 2H), 4.31 (s, 2H), 3.56 (m, 4H), 3.15 (m, 2H) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 160.1, 158.3, 111.5, 85.5, 75.7, 49.9, 44.6, 40.5, 30.7 ppm. C ₁₂ H ₁₇ Cl ₃ N ₄ (323.65).

Example 8

1- (4-chlorobut-2-ynyl) -4- (2-methoxyphenyl) -piperazine dihydrochloride

4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-yn-1-ol dihydrochloride (13.3 g; 40 mmoIes) in thionyl chloride (40 ml; 0.55 mole) ) Was added in a small amount with a spatula under stirring. Upon completion of the addition, the reaction mixture was allowed to warm to reflux temperature. Strong gas formation can be observed, the starting material is dissolved and the product is separated in the form of a salt. 30 ml of toluene was added to the reaction mixture and stirred until gas formation stopped. The mixture was then cooled and the white powder was filtered off, washed with ethyl acetate and dried. Yield: 12.52 g white powder (89%).

Mp: 174-175 ° C. (CH ₃ CN).

IR (KBr): 2400, 2200 cm ^-1 .

¹ H-NMR (D ₂ 0, DSS, 200 MHz): 7.51-7.43 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 4.41 ( s, 2H), 4.35 (s, 2H), 3.99 (s, 3H), 3.87 (br s, 8H) ppm.

¹³ C-NMR (D ₂ 0, DSS, 50 MHz): 154.3, 134.2, 132.2, 124.2, 122.9, 115.6, 89.6, 75.7, 58.5, 52.1, 48.7, 32.3 ppm.

C ₁₅ H ₂₁ Cl ₃ N ₂ 0 (351.70).

Example 9

1- (2,6-dichlorophenyl) -3-isopropylidene-1,3-di-hydro-2H-indol-2-one

1- (2,6-dichlorophenyl) -oxindole (27.8 g; 0.10 mole) is dissolved in 300 ml of acetone, pyrrolidine (10 ml; 0.12 mole) is metered into the solution, which is warmed at reflux temperature It was. The reaction mixture was refluxed for 3 hours and the solution was evaporated. The product, separated in crystalline form, was dissolved in dichloro-methane and extracted twice with 10% hydrogen chloride, and the organic phase was dried over sodium sulfate, clarified with bone char, filtered and evaporated. The product was used for catalytic hydrogenation without recrystallization. Analytical samples can be obtained by recrystallization from ethyl acetate. Yield: 31.82 g yellow crystals (97%).

M.p .: 180-182 ° C. (ethyl acetate).

] R (KBr): 1700 (C = O), 793 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 2.46 (3H, s), 2.66 (3H, s), 6.40 (1H, dd, J = 0.6, 7.8 Hz), 7.09 (1H, dt, J = 1.2, 7.6 Hz), 7.17 (1H, dt, J = 1.0, 7.6 Hz), 7.35 (1H, dd, J = 7.6, 8.7 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.64 (1H, d, J = 7.5 Hz ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 23.4, 25.4, 108.5, 122.0, 122.3, 123.7, 123.8, 127.6, 128.9, 130.4, 130.9, 135.9, 140.0, 156.1, 166.2 ppm.

Anal for Formula C ₁₇ H ₁₃ Cl ₂ NO (318.21):

Calc. For C 64.17, H 4.12, Cl 22.28, N 4.40%.

Found: C 64.02, H 4.11, Cl 22.14, N 4.39%

Example 10

1- (2,6-dichlorophenyl) -3-isopropyl-1,3-dihydro-2H-indol-2-one

1- (2,6-dichlorophenyl) -3-isopropylidene oxindole (23.7 g; 75 mmoles) is dissolved in 170 ml of methanol, palladium on 5% bone char (2.0 g) is added thereto and the reaction The mixture was stirred in an autoclave for 3 hours at room temperature under 15 bar starting hydrogen pressure. It was then clarified with bone char, filtered and evaporated. The remaining yellow oil becomes a crystal-share upon grinding with hexane. The product was stirred in hexane, filtered, dried and used without further purification. Yield: 19.6 g off-white powder (82%).

M.p .: 138-140 ° C. (ethyl acetate).

IR (KBr): 1720 (C = 0), 752 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.09 (dt, J = 0.9, 7.5 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 3.64 (d, J = 3.5 Hz, 1H), 2.63 (m, 1H), 1.20 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 175.8, 142.8, 135.5, 135.4, 130.6, 130.5, 129.0, 128.9, 127.7, 127.6, 122.7, 121.7, 108.8, 51.7, 31.0, 20.1, 18.7 ppm.

C ₁₇ H ₁₅ Cl ₂ NO (320.22).

Example 11

1- (2,6-dichlorophenyl) -3-isopropyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3- Dihydro-2H-indol-2-one monohydrochloride

Sodium hydride (2.7 g; 55% suspension; 62 mmoles) was washed three times with each 10 ml of hexane to remove the suspended oil and suspended in 100 ml of DMF at room temperature. 1- (2,6-dichlorophenyl) -3-isopropyl-oxindole (5.0 g; 15.6 mmoles) was added thereto in small amounts. When gas formation ceased, a small amount of 2- [4- (4-chlorobut-2-ynyl) -piperazin-1-yl] -pyrimidine di-hydrochloride (4.88 g; 15.1 mmoles) was added thereto It was. The mixture was allowed to react for 1 hour. 2 ml of water was then added thereto to decompose the excess sodium hydride. The mixture was extracted with water and diethyl ether and the aqueous phase was extracted again with ether. The combined organic phases were dried over sodium sulphate and evaporated. The tan oil thus obtained was purified by column chromatography using ethyl acetate as eluent. Pure material was dissolved in 100 ml of diethyl ether and 1 molar equivalent of hydrogen chloride solution in isopropanol was added dropwise to the solution under stirring. The separated hydrochloride salt was filtered off, washed with a small amount of IPA and hexanes and dried in vaccum pistol. Yield: 3.02 g white powder (37%).

M.p .: 171-173 ° C.

IR (KBr): 2364, 1722 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 13.3 (1H, s), 8.35 (2H, d, J = 4.7 Hz), 7.54-7.49 (2H, m), 7.40 (1H, t, J = 7.6 Hz), 7.28 (1H, d, J = 6.8 Hz), 7.11 (1H, dt, J = 1.2, 7.6 Hz), 6.91 (1H, dt, J = 0.9, 7.6 Hz), 6.62 (lH, t, J = 4,8 Hz), 6.40 (1H, d, J = 7.8 Hz), 4.85, 4.76 (2xlH, d, J = 14.4 Hz), 3.83, 3.68 (2x1H, d, 17.1 Hz), 3.62. 3.59 (2xlH, d, J = 11.7 Hz), 3.14, 3.01 (2xlH d, J = 11.0 Hz), 2.97, 2.91 (2x1H d, J = 17.1 Hz), 2.88 (1H, m), 2.46 (1H, m ), 2.30 (1H, q, J = 6.9 Hz), 1.03 (3H, d, J = 6.9 Hz), 0.98 (3H, d, J = 6.9 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz) 176.4, 157.7, 150.8, 142.2, 135.1, 135.0, 130.8, 130.1, 129.9, 129.3, 129.2, 128.3, 124.0, 123.0, 111.2, 109.1, 88.8, 69.2, 54.8, 49.5, 46.4, 40.3, 34.9, 25.7, 17.4 ppm.

Anal for Formula C ₂₉ H ₃₀ Cl ₃ N ₅ 0 (570.95):

Calc. For C 61.01, H 5.30, Cl 18.63, N 12.27%.

Found: C 59.81, H 5.28, Cl 18.41, N 11.90%.

Example 12

(E) -1- (2,6-dichlorophenyl) -3- (4-methyl-benzylidene) -1,3-dihydro-2H indol-2-one

1- (2,6-dichlorophenyl) -oxindole (22.24 g; 80 mmoles) and 4-methyl benzaldehyde (10.0 g; 84 mmoles) are dissolved in 250 ml of toluene and pyrrolidine (4.0 ml; 0.30 mole ) Was weighed into solution and the mixture was warmed to reflux. It was refluxed for 1 hour, allowed to cool, extracted twice with 10% hydrogen chloride, the toluene phase was dried over sodium sulfate, clarified with bone char, filtered, washed with toluene on a filter and evaporated. The remaining orange-red oil became crystalline upon trituration with hexane. The material was stirred in hexanes, filtered and washed with hexanes. The product was used for catalytic hydrogenation without recrystallization. Yield: 18.59 g yellow crystals (61%).

M.p .: 201-202 ° C. (ethyl acetate).

IR (KBr): 1716 (C = O), 791 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 2.44 (3H, s), 6.41 (1H, d, J = 7.9 Hz), 6.95 (1H, t, J = 7.7 Hz), 7.18 (1H, t , J = 7.7 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.37 (1H, t, J = 7.7 Hz), 7.51 (1H, d, J = 7.9 Hz), 7.64 (2H, d, J = 8.0 Hz), 7.81 (1H, d, J = 7.7 Hz), 7.96 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 21.6, 109.2, 121.4, 122.4, 123.0, 125.5, 128.9, 129.3, 129.5, 129.6, 130.5, 130.6, 131.8, 135.7, 138.8, 140.2, 142.1, 167.2 ppm .

Analysis for formula C ₂₂ H ₁₅ Cl ₂ NO (380.28):

Calculated: C 69.49, H 3.98, Cl 18.65, N 3.68%.

Found: C 69.53, H 4.03, Cl 18.49, N 3.67%.

Example 13

1- (2,6-dichlorophenyl) -3- (4-methylbenzyl) -1,3-dihydro-2H-indol-2-one

1- (2,6-dichlorophenyl) -3- (4-methyl-benzylidene) -oxindole (12.0 g; 31.6 mmoles) was dissolved in 170 ml of ethanol and the palladium catalyst on 5% bone char (2.0 g) And saturated in the autoclave under a hydrogen pressure of 10 bar. The reaction was run for 2 hours. The catalyst was then filtered off and the mixture was clarified with bone char and evaporated. The product became crystalline in the form of an off-white powder. Yield: 10.21 g off-white powder (84%).

M.p .: 123-124 ° C. (hexane-ethyl acetate).

IR (KBr): 1718 (C = O), 753 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.47 (dd, J = 1.4, 8.0 Hz, 1H), 7.45 (dd, J = 1.4, 8.2 Hz, 1H), 7.33 (t, J = 8.1 Hz , 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.97 (dt, J = 0.9, 7.5 Hz , 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 3.96 (dd, J = 4.5, 9.2 Hz, 1H), 3.57 (dd, J = 4.5, 13.7 Hz, 1H), 3.03 (dd, J = 9.2, 13.7 Hz, 1H), 2.31 (s, 3H) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 175.5, 142.4, 136.2, 135.5, 135.4, 134.5, 130.6, 130.1, 129.5, 129.0, 128.9, 128.8, 127.9, 126.2, 125.0, 122.6, 108.9, 47.2, 36.5, 21.0 ppm.

C ₂₂ H ₁₇ Cl ₂ NO (382.29).

Example 14

1- (2,6-dichlorophenyl) -3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-ynyl} -3- (4-methylbenzyl) -1,3-dihydro-2H-indol-2-one dioxalate

Sodium hydride (2.0 g; 55% suspension; 46 mmoles) was washed three times with each 10 ml of hexane to remove suspended oil and suspended in 50 ml of DMF at room temperature. A small amount of 1- (2,6-dichlorophenyl) -3- (4-methylbenzyl) -oxindole (5.0 g; 13 mmoles) was added thereto, and when formation of hydrogen gas was stopped, 1- (4 -Chlorobut-2-ynyl) -4- (2-methoxyphenyl) -piperazine dihydrochloride (4.61 g; 13 mmoles) was added thereto in small amounts. After 1 hour, 2 ml of water was added to the reaction mixture to decompose excess sodium hydride. The mixture was extracted with water and ethyl acetate, the organic phase was oxidized with 10% by volume hydrogen chloride solution, the acidic-phase was made alkaline again with 25% by volume ammonia solution and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated. The remaining tan oil (7.0 g; 11.2 mmoles) was dissolved in 70 ml of hot ethyl acetate, and a solution of oxalic acid dihydrate (2.82 g; 22.4 moles) in 30 ml of hot ethyl acetate was added dropwise. The reaction mixture was cooled to separate the dioxalate salt. It was filtered and washed with ethyl acetate and hexanes. Yield: 7.88 g white powder (75%).

M.p .: 167-170 ° C.

IR (KBr): 1712 (C = O), 753 cm ^-1 .

¹ H-NMR (CD ₃ OD, TMS, 400 MHz): 7.60 (1H, m), 7.58 (1H, doublet of doublets, J = 2.2, 7.3 Hz), 7.48-7.41 (1H, m), 7.47 (1H, t , J = 8.2 Hz), 7.21-7.13 (2H, m), 7.06 (1H, dt, J = 0.9, 1.8 Hz), 6.98-6.89 (3H, m), 6.86 (2H, d, J = 7.9 Hz) , 6.81 (2H, d, J = 8.1 Hz,), 6.26 (1H, dd, J = 1.2, 8.3 Hz), 4.09, 3.94 (2x1H, d, J = 16.0 Hz), 3.82 (3H, s), 3.38 , 3.22 (2x1H, d, J = 13.3 Hz), 3.09, 2.99 (2x 1H, d, J = 16.8 Hz), 3.4-3.0 (8H, br s), 2.18 (3H, s) ppm.

¹³ C-NMR (CD ₃ OD, TMS, 101 MHz): 178.5, 164.3, 154.0, 143.4, 140.5, 137.7, 133.0, 132.7, 131.7, 131.5, 131.1, 130.8, 130.4, 130.3, 130.3, 129.8, 129.0, 126.2, 125.6, 124.7, 122.3, 120.8, 120.1, 113.1, 110.0, 88.5, 72.6, 56.2, 54.0, 52.5, 48.9, 47.3, 42.8, 28.8, 21.2 ppm.

Anal for Formula C ₄₁ H ₃₉ Cl ₂ N ₃ 0 ₁₀ (804.69):

Calc. For C 61.20, H 4.89, Cl 8.81, N 5.22%.

Found: C 61.12, H 5.00, Cl 8.73, N 5.25%.

Example 15

3-ethyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one

2.5 M n-butyl lithium (60 ml; 0.15 mole) was weighed into the flask washed with argon. 40 ml of THF was added thereto and the solution was cooled to -78 ° C in an acetone-dried ice bath. At this temperature, a solution of 3-ethyl oxindole (9.66 g; 0.06 mole) in 50 ml of THF is added dropwise under stirring, stirred for a further 10 minutes, and propargyl bromide (4.7 ml; 0.063 mole) is excited here. Was added drop wise and the solution was allowed to warm to room temperature. It was then stirred for an additional 3 hours and 20 ml of ethanol was added dropwise to decompose excess butyl lithium. The solution was distilled off on a rotary evaporator and the remaining oil was extracted with water and ethyl acetate. The organic phase was dried over sodium sulfate. The remaining oil was crystalline by trituration with hexanes. The isolated off-white crystals were stirred in 50 ml of hexane to remove excess propargyl bromide, filtered and washed with hexane. The product was used for the next reaction without recrystallization. Yield: 10.87 g white powder (91%).

M.p .: 108-110 ° C. (hexane-ethyl acetate).

IR (KBr): 3308, 3150, 1719 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 200 MHz): 9.19 (br s, 1H, NH), 7.36 (dt, 1H, J = 7.3, 0.7 Hz, H-4), 7.24 (dt, 1H, J = 7.7, 1.5 Hz, H-6), 7.07 (dt, 1H, J = 7.7, 1.1 Hz, H-5), 6.96 (d, 1H, J = 7.7 Hz, H-7), 2.65 (dq, 2H, J = 16.5, 2.6 Hz, CH ₂ CCH), 2.10-1.88 (m, 2H, CH ₂ CH ₃ ), 1.94 (t, 1H, J = 2.6 Hz, CH), 0.67 (t, 3H, J = 7.3 Hz , CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 50 MHz): 181.4, 141.2, 131.4, 128.1, 123.6, 122.4, 109.8, 79.5, 70.7, 52.3, 29.1, 27.0, 8.6 ppm.

Analysis for formula C ₁₃ H ₁₃ NO (199.25):

Calculated: C 78.36, H 6.58, N 7.03%.

Found: C 78.29, H 6.55, N 6.99%.

Example 16

3-ethyl-1-methyl-3- (prop-2-ynyl) -1,3-dihydro-2H indol-2-one

Sodium hydride (331 g; 55% suspension; 85 mmoles) was washed three times with about 10 ml of hexane and suspended in 70 ml of DMF. The reaction mixture was cooled to 0-2 ° C. and at this temperature a solution of 3-ethyl-3- (prop-2-ynyl) -oxindole (15.0 g; 75 mmoles) in 60 ml of DMF was added dropwise thereto. . When hydrogen formation ceased, methyl iodide (5.3 ml; 85 mmoles) was added dropwise to the reaction mixture, which was stirred for 3 hours, 5 ml of water was added dropwise to decompose excess sodium hydride, water and diethyl ether Extracted with. The organic phase was dried over sodium sulfate, clarified with bone char, filtered and evaporated. The remaining pale yellow oil was triturated with hexanes to crystalline. Yield: 12.21 g of off-white powder (76%).

M.p .: 79-81 ° C. (hexane-ethyl acetate).

IR (KBr): 2970, 2930, 1710 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 200 MHz): 7.39. (d, J = 7.3 Hz, 1H), 7.30 (dt, J = 1.1, 7.7, 1H), 7.09 (dt, J = 1.1, 7.6 Hz, 1H), 3.22 (s, 3H), 2.71, 2.51 (dd , J = 2.5, 16.5 Hz, 2H), 2.00 (q, J = 7.3 Hz, 2H), 1.92 (t, J = 2.8 Hz, 1H), 0.59 (t, J = 7.5 Hz, 3H) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 50 MHz): 178.5, 143.8, 130.9, 128.1, 123.2, 122.4, 107.7, 79.5, 70.4, 51.5, 29.0, 26.9, 26.0, 8.5 ppm.

Analysis for formula C ₁₄ H ₁₅ NO (213.28):

Calculated: C 78.84, H 7.09, N 6.57%.

Found: C 78.44, H 7.08, N 6.52%.

Example 17

1-benzyl-3-ethyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one

Sodium hydride (3.71 g; 55% suspension; 85 mmoles) was washed three times with 10 ml of hexane each and suspended in 70 ml of DMF. The reaction mixture was cooled to 0-2 ° C. and at this temperature a solution of 3-ethyl-3- (prop-2-ynyl) -oxindole (15.0 g; 75 mmoles) in 60 ml of DMF was added dropwise. Benzyl chloride (9.5 ml; 75 mmoles) was added dropwise to the mixture when hydrogen gas formation ceased. It was stirred for 2 hours and 5 ml of water was added dropwise to decompose the excess sodium hydride and extracted with water and diethyl ether. The organic phase was dried over sodium sulphate, clarified with bone char, filtered and evaporated. The remaining pale yellow oil was triturated with hexanes to crystalline. Yield: 18.71 g of off-white powder (86%).

M.p .: 79-80 ° C. (hexane-ethyl acetate).

IR (KBr): 1703 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.38-7.20 (m, 6H), 7.17 (dt, J = 1.2, 7.7 Hz, 1H), 7.05 (dt, J = 1.0, 7.6 Hz, 1H) , 6.73 (d, J = 7.8 Hz, 1H), 4.96, 4.90 (d, J = 15.7 Hz, 2H), 2.75, 2.62 (dd, J = 2.7, 16.5 Hz, 2H), 2.02 (q, J = 7.4 Hz, 2H), 1.87 (t, J = 2.7 Hz, 1H), 0.64 (t, J = 7.4 Hz, 3H) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 178.6, 143.1, 135.9, 130.9, 128.6, 128.0, 127.5, 127.3, 123.3, 122.5, 108.9, 79.6, 70.6, 51.7, 43.7, 29.4, 27.2, 8.7 ppm .

Analysis for formula C ₂₀ H ₁₉ NO (289.38):

Calc. For C 83.01, H 6.62, N 4.84%.

Found: C 82.91, H 6.67, N 4.80%.

Method A (Manish Reaction of Acetylene Hydrogen with Piperazine)

35% aqueous formalin solution (50 ml) in a mixture of suitable N-substituted 3-propargyl oxindole (50 mmoles), suitable piperazine (50 mmoles), 1.0 g of copper (II) acetate monohydrate and 100 ml of ethanol 0.63 mole) was added dropwise and the solution was refluxed for 2 hours. It was filtered over a G4 glass filter to remove polymeric formaldehyde, evaporated and extracted with water and ethyl acetate. The organic phase was clarified with bone char, dried over sodium sulfate and evaporated. The remaining pale yellow oil was purified by column chromatography using ethyl acetate as eluent.

Purification Method 1 : Calculated amount (1 or 2 molar equivalent (s)) in ether diluted with basic product in 200 ml of ether, small amount of suspended precipitate filtered and diluted with 50 ml of diethyl ether in pure solution Hydrogen chloride solution was added dropwise under strong stirring at room temperature within 30 minutes. The separated white salt was filtered off, washed with ether and hexanes and dried in vacuo pistol for 3 hours at room temperature. If necessary, the hydrochloride salt was recrystallized.

Purification Method 2 : If the basic product did not become crystalline upon addition of diethyl ether and provided a salt that could be well-filtered with hydrogen chloride, it was dissolved in 200 ml of hot ethyl acetate and 1 in 50 ml of hot ethyl acetate. A molar equivalent of oxalic acid dihydrate solution was added dropwise thereto with stirring within 10 minutes. The white oxalate salt was separated after cooling. It was filtered at room temperature, washed with ethyl acetate and hexanes and dried.

Example 18

3-ethyl-3- (4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-ynyl} -1-methyl-1,3-dihydro-2H-indole- 2-one dihydrochloride

Title compound is 3-ethyl-1-methyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 1- (2-methoxy-phenyl) -piperazine Prepared according to Method A by applying Purification Method 1 starting from.

M.p .: 189-192 ° C.

IR (KBr): 2840, 1710 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): kb. 13.7 (1H, br s), 8.17 (1H, d, J = 7.6 Hz), 7.46 (1H, dt, J = 1.5, 7.9 Hz), 7.37 (1H, dd, J = 0.6, 7.3 Hz), 7.25 ( 1H, dd, J = 1.1, 7.7 Hz), 7.11-7.03 (3H, m), 6.91 (1H, d, J = 7.8 Hz), 4.8 (2H, m), 4.10 (1H, m), 4.06 (3H , s), 4.01 (1H, m), 3.85 (2H, m), 3.50 (2H, m), 3.36 (1H, d, J = 12.5 Hz), 3.29 (3H, s), 3.21 (1H, d, J = 12.5 Hz), 2.85, 2.78 (2H, d, J = 16.8 Hz), 2.05-1.83 (2H, m), 0.60 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 178.0, 152.4, 144.2, 131.4, 130.6, 128.6, 128.0, 123.7, 123.4, 122.4, 121.6, 113.3, 108.0, 68.2, 55.9, 52.1, 48.5, 47.3, 47.1, 46.0, 29.6, 27.1, 26.2, 8.5 ppm.

Anal for Formula C ₂₆ H ₃₃ Cl ₂ N ₃ 0 ₂ (490.48):

Calc. For C 63.67, H 6.78, Cl 14.46, N 8.57%.

Found: C 62.99, H 6.84, Cl 13.84, N 8.65%.

Example 19

3-ethyl-1-methyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H-indole-2 -On monooxalate

The title compound is referred to as 3-ethyl-1-methyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 2- (piperazin-1-yl) -pyrimidine Prepared according to Method A by applying Purification Method 2 starting from.

Mp: 119-121 ° C.

IR (KBr): 3452, 1702 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 8.5 (2H, broad s), 8.44 (2H, d, J = 4.8 Hz), 7.35 (1H, dd, J = 1.8, 7.3 Hz), 7.13 (1H, dt, J = 1.3, 7.7 Hz), 7.00 (1H, dt, J = 0.9, 7.5 Hz), 6.74 (1H, d, J = 7.8 Hz), 3.70 (4H, s), 3.48, 3.36 (1 + 1H, d, J = 16.6 Hz), 3.07 (3H, s), 2.79, 2.60 (1 + 1H, d, J = 16.3 Hz), 2.34-2.27 (4H, m), 1.81-1.72 (2H , m), 0.46 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 177.9, 162.5, 161.1, 158.2, 144.2, 130.8, 128.0, 123.2, 122.3, 110.6, 108.1, 82.9, 74.2, 52.3, 50.0, 45.8, 42.1, 29.4, 26.5, 25.9, 8.7 ppm.

Analysis for Formula C ₂₅ H ₂₉ N ₅ 0 ₅ (479.54):

Calculated: C 62.62, H 6.10, N 14.60%.

Found: C 62.62, H 6.28, N 14.30%.

Example 20

3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -but-2-ynyl} -3-ethyl-1-methyl-1,3-dihydro-2H-indole-2 -On monooxalate

The title compound was obtained from 3-ethyl-1-methyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 1- (4-chloro-phenyl) -piperazine. Prepared according to Method A by starting purification method 2.

M.p .: 69-72 ° C.

IR (KBr): 3453, 1710 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.78 (3H, broad singlet), 7.26-7.21 (4H, m), 7.08 (1H, dt, J = 0.8, 7.5 Hz), 6.83-6.78 (3H , m), 3.7 (2H, br s), 3.26 (4H, br s), 3.20 (3H, s), 2.87 (4H, br s), 2.78 (1H, d, J = 16.7 Hz), 2.71 (1H , d, J = 16.7 Hz), 1.96-1.79 (2H, m), 0.58 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 178.2, 164.0, 148.3, 143.9, 130.6, 129.1, 128.1, 125.9, 122.9, 122.7, 117.7, 107.9, 86.5, 70.0, 52.4, 49.6, 46.7, 45.7, 30.0, 26.9, 26.1, 8.5 ppm

Analysis for Formula C ₂₇ H ₃ 0ClN ₃ 0 ₅ (512.01):

Calc. For C 63.34, H 5.91, Cl 6.92, N 8.21%.

Found: C 63.43, H 5.97, Cl 6.99, N 8.20%.

Example 21

3-ethyl-1-methyl-3- [4- (4-phenylpiperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H-indol-2-one monooxalate

Purification Method 2 was carried out starting from 3-ethyl-1-methyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 1-phenyl-piperazine. Application was made according to Method A.

M.p .: 73-76 ° C.

IR (KBr): 3453, 1710 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.71 (3H, broad singlet), 7.32-7.22 (4H, m), 7.08 (1H, dt, J = 0.8, 7.5 Hz), 6.94 (1H, t , J = 7.3 Hz), 6.89 (2H, d, J = 7.9 Hz), 6.81 (1H, d, J = 7.7 Hz), 3.77 (2H, s), 3.31 (4H, br s), 3.20 (3H, s), 2.95 (4H, br s), 2.79 (1H, d, J = 16.6 Hz), 2.71 (1H, d, J = 16.6 Hz), 2.04-1.77 (2H, m), 0.58 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 178.1, 163.5, 149.4, 143.9, 130.5, 129.2, 128.1, 122.9, 122.7, 121.1, 116.6, 108.0, 87.2, 69.2, 52.3, 49.7, 46.4, 45.6, 29.9, 26.8, 26.0, 8.4 ppm.

Anal for Formula C ₂₇ H ₃₁ N ₃ 0 ₅ (477.57):

Calculated: C 67.91, H 6.54, N 8.80%.

Found: C 67.20, H 6.60, N 8.73%.

Example 22

1-benzyl-3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-ynyl} -1,3-di hydro-2H-indole- 2-one monohydrochloride

Title compound is 3-ethyl-1-benzyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 1- (2--methoxy-phenyl) -pipe Prepared according to Method A by applying Purification Method 1 starting from Razine.

M.p .: 199-202 ° C.

IR (KBr): 2337, 1713 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.4-7.2 (5H, m), 7.25 (1H, doublet of doublets, J = 1.0, 7.3 Hz), 7.14 (1H, dt, J = 1.3, 7.7 Hz) , 7.10-7.04 (2H, m), 6.97-6.88 (3H, m), 6.81 (1H, d, J = 7.7 Hz), 5.02, 4.92 (2H, d, J = 15.4 Hz), 3.87 (3H, s ), 3.64, 3.45 (2H, d, J = 16.8 Hz), 3.35 (4H, br s), 2.88, 2.77 (2H, d, J = 16.6 Hz), 3.00-2.60 (4H, s), 2.02, 1.91 (2H, m), 0.66 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 178.2, 151.8, 143.2, 138.7, 135.9, 130.5, 128.7, 128.2, 127.9, 127.7, 124.2, 123.1, 122.7, 121.2, 118.8, 111.3, 108.9, 88.0, 68.8, 55.2, 52.3, 50.0, 47.0, 45.8, 43.7, 29.9, 27.6, 8.8 ppm.

Anal for Formula C ₃₂ H ₃₆ ClN ₃ O ₂ (530.12):

Calc. For C 72.50, H 6.85, Cl 6.69, N 7.93%.

Found: C 72.16, H 6.83, Cl 6.50, N 7.89%.

Example 23

1-benzyl-3-ethyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H-indole-2 -On monooxalate

The title compound is referred to as 3-ethyl-1-benzyl-3- (prop-2-ynyl) -1,3-dihydro-2H-indol-2-one and 2- (piperazin-1-yl) -pyrimidine Prepared according to Method A by applying Purification Method 2 starting from.

M.p .: 154-155 ° C.

IR (KBr): 1716 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 10.83 (2H, broad singlet), 8.39 (2H, d, J = 4.8 Hz), 7.40-7.25 (5H, m), 7.15 (1H, d, J = 7.3 Hz), 7.02 (1H, dt, J = 1.1, 7.7 Hz), 6.87 (1H, t, J = 7.2 Hz), 6.70 (1H, d, J = 7.8 Hz), 6.64 (1H, t, J = 4.8 Hz), 4.95 (1H, d, J = 15.3 Hz), 4.77 (1H, d, J = 15.3 Hz), 3.90 (4H, s), 3.71 (1H, d, J = 16.8 Hz), 3.41 ( 1H, dt, J = 16.8, 2.2 Hz), 2.88 (1H, d, J = 16.6 Hz), 2.72 (1H, dt, J = 16.6, 2.3 Hz), 2.50 (4H, br s), 1.96 (1H, m), 1.82 (1H, m), 0.63 (3H, t, J = 7.3 Hz) ppm.

¹³ C NMR (CDCl ₃ , TMS, 101 MHz): 178.2, 163.1, 160.8, 157.8, 143.1, 136.0, 130.5, 128.8, 128.3, 128.0, 127.9, 122.9, 122.7, 111.3, 108.7, 87.5, 69.1, 52.4, 49.6, 45.7 , 43.8, 40.2, 30.2, 27.2, 8.7 ppm.

Anal for Formula C ₃₁ H ₃₃ N ₅ O ₅ (555.64):

Calc .: C 67.01, H 5.99, N 12.60%.

Found: C 66.44, H 6.00, N 12.44%.

Method B (catalytic hydrogenation of triple bonds to single bonds)

Compounds containing triple bonds (6 mmoles) are dissolved in 20 ml of methanol, weighed with 70 ml of autoclave, 5% palladium on bone charcoal (0.30 g) is added thereto, saturated at 10 bar hydrogen pressure. I was. After 2 hours, the solution was filtered and evaporated. The remaining product was a yellow oil.

Purification Method 1 : The oil is dissolved in 200 ml of ether, a small amount of suspended precipitate is filtered off, and a pure solution of a calculated amount (1 molar equivalent) of hydrogen chloride solution in 50 ml of diethyl ether in 30 minutes at room temperature is concentrated. It was added dropwise under stirring. The separated white salt was filtered off, washed with ether and hexanes and dried in vacuo pistol for 3 hours at room temperature. If necessary, the hydrogen chloride salt was recrystallized.

Purification Method 2 : If the basic product does not provide a salt that can be well-filtered with hydrogen chloride, dissolve it in 200 ml of hot ethyl acetate and stir 1 molar equivalent of oxalic acid dihydrate solution in 50 ml of hot ethyl acetate Drop wise in 10 minutes. The white oxalate salt was separated by cooling. It was filtered at room temperature, washed with ethyl acetate and hexanes and dried.

Example 24

1-benzyl-3-ethyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one monooxal Rate

The title compound is 1-benzyl-3-ethyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H- Prepared according to Method B by applying Purification Method 2 starting from indole-2-one.

M.p .: 145-146 ° C.

IR (KBr): 1702 (C = O) cm ^-1 .

_{^{l H-NMR (CDCl 3,}} TMS, 400 MHz): 10.0 (1H, br s), 7.30-7.20 (5H, m), 7.17 (1H, t, J = 7.6 Hz), 7.13 (1H, d, J = 6.7 Hz), 7.05 (1H, t, J = 7.4 Hz), 6.61 (lH, t, J = 4.8 Hz), 4.98, 4.83 (2H, d, J = 15.6 Hz), 4.13 (4H, br s), 3,10 (4H, br s), 2.84 (2H , m), 1.95 (2H, m), 1.84-1.74 (2H, m), 1.60 (2H, m), 1.01-0.84 (2H, m), 0.59 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 179.7, 163.2, 160.8, 157.9, 143.1, 136.1, 131.4, 128.7, 127.8, 127.6, 127.4, 122.8, 122.7, 111.4, 108.9, 57.1, 53.2, 51.8, 43.7, 40.8, 36.9, 31.2, 23.4, 21.6, 8.6 ppm

Anal for Formula C ₃₁ H ₃₇ N ₅ 0 ₅ (559.67):

Calc. For C 66.53, H 6.66, N 12.51%.

Found: C 65.88, H 6.65, N 12.45%.

Example 25

1-benzyl-3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -butyl) -1,3-dihydro-2H-indol-2-one mono Oxalate

The title compound is 1-benzyl-3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-ynyl) -1,3-dihydro-2H Prepared according to Method B by applying Purification Method 2 starting from indole-2-one.

M.p .: 128-129 ° C.

IR (KBr): 3432, 1704 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.32-7.21 (5H, m), 7.18 (1H, dt, J = 1.3, 7.7 Hz), 7.13 (1H, d, J = 6.5 Hz), 7.06 (2H, m), 6.90 (3H, m), 6.77 (lH, d, J = 7.7 Hz,), 5.7 (2H, br s), 4.99, 4.84 (2x1H, d, J = 15.4 Hz), 3.86 ( 3H, s), 3.58 (2H, dd, J = 11.6, 27.6), 3.46 (2H, m), 3.25 (2H, m), 2.97 (2H, t, J = 10.6 Hz), 2.85 (2H, m) , 1.96 (2H, m), 1.81 (2H, m), 1.67 (2H, q, J = 8.0 Hz), 0.95 (2H, m), 0.60 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 179.8, 163.0, 151.9, 143.1, 136.8, 136.1, 131.4, 129.6, 128.6, 127.8, 127.6, 127.6, 127.4, 122.8, 122.7, 121.1, 118.7, 111.6, 108.9, 57.0; 55.4, 53.4, 52.4, 47.5, 43.7, 36.9, 31.1, 23.4, 21.6, 8.6 ppm.

Analysis for Formula C ₃₄ H ₄₁ N ₃ 0 ₆ (587.72):

Calc. For C 69.49, H 7.03, N 7.15%.

Found: C 69.08, H 6.94, N 7.13%.

Example 26

3-ethyl-1-methyl-3- [4- (4-phenylpiperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one monohydrochloride

Title compound starts from 3-ethyl-1-methyl-3- [4- (4-phenylpiperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H indol-2-one Was prepared according to Method B by applying Purification Method 1.

M.p .: 219-222 ° C.

IR (KBr): 2370, 1711 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 12.8 (1H, broad singlet), 7.4-7.35 (4H, m), 7.28 (1H, t, J = 7.5 Hz), 7.18 (1H, m), 7.13 (1H, d, J = 6.7 Hz), 7.09 (1H, t, J = 7.3 Hz), 6.85 (1H, d, J = 7.8 Hz), 4.10 (2H, br s), 3.65-3.50 (6H, m), 3.21 (3H, s), 2.97 (2H, br s), 2.03-1.70 (6H, m), 1.07-0.89 (2H, m), 0.54 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 179.3, 143.7, 131.1, 129.7, 127.7, 125.5, 122.4, 118.8, 107.7, 56.6, 53.1, 50.1, 49.8, 48.4, 36.3, 30.7, 25.8, 23.2, 21.3, 8.2 ppm.

Anal for Formula C ₂₅ H ₃₄ ClN ₃ 0 (428.02):

Calc. For H 8.01, N 9.82%.

Found: H 7.56, N 9.35%.

Example 27

3-ethyl-1-methyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one monooxal Rate

The title compound is 3-ethyl-1-methyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H indole Prepared according to Method B by applying Purification Method 2 starting from 2-one.

Mp: 150-152 ° C.

IR (KBr): 1706 (C = 0) cm ^-1

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9,7 (2H, broad singlet), 8.33 (2H, d, J = 4.8 Hz), 7.28 (1H, dt, J = 1.8, 7.5 Hz), 7.12 (1H, dd, J = 1.5, 7.2 Hz), 7.09 (1H, t, J = 7.3 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.60 (1H, t, J = 4.8 Hz), 4.14 (4H, br s), 3.20 (3H s), 3.15 (4H, br s), 2.88 (2H, m), 1.91 (1H, m), 1.88 (1H, m), 1.74 (2H, m), 1.62 (2H, m), 0.54 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 179.7, 163.2, 160.8, 157.8, 143.9, 131.3, 127.9, 122.7, 122.6, 111.3, 107.9, 57.1, 53.3, 51.8, 40.7, 36.5, 31.0, 26.0, 23.4, 21.6, 8.4 ppm.

Anal for Formula C ₂₅ H ₃₃ N ₅ O ₅ (483.57):

Calc. For C 62.10, H 6.88, N 14.48%.

Found: C 61.99, H 6.89, N 14.45%.

Method C (Bromination of Butinol Compounds)

Suitable substituted piperazin-1-yl-but-2-yn-1-ol dihydrochloride (20 mmoles) was metered into 50 ml of phosphorus tribromide and allowed to react at 100 ° C. for 2 hours. It was cooled and 20 ml of dichloromethane were added and the off white material was filtered off and used for the coupling reaction without further purification.

Example 28

1- (4-bromobut-2-ynyl) -4- (2-methoxyphenyl) -piperazine dihydrochloride

The title compound was prepared according to Method C starting from 4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-yn-1-ol dihydrochloride.

M.p .: 185-190 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 9.8 (2H, br s), 7.14-6.88 (4H, m), 4.47 (2H, s), 4.42 (2H, s), 3.81 (3H , s), 3.00-3.71 (8H, m) ppm.

Example 29

2- [4- (4-Bromobut-2-ynyl) -piperazin-1-yl] -pyrimidine dihydrochloride

The title compound was prepared according to Method C starting from 4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-yn-1-ol dihydrochloride.

Mp : 148-151 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 8.56 (2H, m), 8.4 (2H, br s), 6.87 (1H, m), 4.66 (2H, s), 4.06 (2H, m ), 3.8-3.1 (8H, m) ppm.

Example 30

1- (4-bromobut-2-ynyl) -4-phenylpiperazine dihydrochloride

The title compound was prepared according to Method C starting from 4- (4-phenylpiperazin-1-yl) -but-2-yn-1-ol dihydrochloride.

M.p .: 195-200 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 9.5 (2H, m), 7.27 (2H, t, J = 8.0 Hz), 7.02 (2H, d, J = 7.9 Hz), 6.92 (1H , t, J = 7.0 Hz), 4.43 (2H, s), 4.41 (2H, s), 4.0-3.0 (8H, m) ppm.

Example 31

1- (4-bromobut-2-ynyl) -4- (3-chlorophenyl) -piperazine dihydrochloride

The title compound was prepared according to Method C starting from 4- [4- (3-chlorophenyl) -piperazin-1-yl] -but-2-yn-1-ol dihydrochloride.

M.p .: 168-170 ° C.

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 8.4 (2H, m), 7.28 (1H, t, J = 8.0 Hz), 7.07 (1H, s), 6.98 (1H, d, J = 8.4 Hz), 6.89 (1H, d, J = 8.4 Hz), 4.41 (4H, br s), 4.0 (2H, br s), 3.6 (2H, br s), 3.2 (2H, br s) ppm.

Method D (Coupling of 3-Ethyl Oxindole and Bromobutynyl Compound)

Sodium hydride (6.75 g; 50% suspension; 0.14 mole) was washed three times with 20 ml of hexane each and suspended in 50 ml of DMF. The reaction mixture was cooled to -20 ° C and a solution of 3-ethyl oxindole (6.45 g; 0.04 mmole) in 25 ml of DMF was added dropwise thereto at the same temperature. When hydrogen formation ceased, the hydrochloride salt (0.04 mole) of a suitable bromine compound containing triple bonds dissolved in 75 ml of DMF was added dropwise at -20 ° C. The reaction mixture was stirred for 3 hours, 5 ml of water was added dropwise to decompose the excess sodium hydride and the mixture was extracted with water and diethyl ether. The organic phase was dried over sodium sulfate, clarified with bone char, filtered and evaporated. The remaining pale yellow oil was purified by column chromatography using a 10: 1 mixture of dichloromethane and methanol as eluent.

Purification Method 1 : If the product purified by column chromatography became crystalline upon trituration with diethyl ether, it was filtered and recrystallized from a mixture of hexane and ethyl acetate. The desired compound was obtained in the form of white crystals.

Purification Method 2 : If the basic product does not become crystalline upon addition of diethyl ether, it is dissolved in 100 ml of hot ethyl acetate and 1 molar equivalent of oxalic acid dihydrate solution in 50 ml of hot ethyl acetate is stirred under 10 Dropwise added in minutes. The white oxalate salt was separated by cooling. It was filtered at room temperature, washed with ethyl acetate and hexanes and dried.

Example 32

3-ethyl-3- [4- (4-phenylpiperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H-indol-2-one monooxalate

The title compound was prepared according to Method D by applying Purification Method 2 starting from l- (4-bromobut-2-ynyl) -4-phenyl-piperazine dihydrochloride.

M.p .: 94-95 ° C.

IR (KBr): 3210, 1715 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.99 (1H, broad singlet), 7.28-7.20 (2H, m), 7.12 (1H, d, J = 7.3 Hz), 7.06 (1H, t, J = 7.5 Hz), 6.99-6.86 (5H, m), 3.84, 3.67 (2x1H, d, J = 16.5 Hz), 3.27 (4H, br s), 2.89 (4H, br s), 2.76, 2.62 (2xlH, d, J = 16.4 Hz), 1.87 (2H, m), 0.63 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.7, 164.3, 149.6, 142.3, 131.1, 129.2, 127.9, 122.7, 122.1, 120.9, 116.6, 110.7, 86.9, 69.5, 53.3, 49.9, 46.4, 45.6, 29.7, 27.2, 8.7 ppm.

Anal for Formula C ₂₆ H ₂₉ N ₃ O ₅ (462.54):

Calculated: C 67.37, H 6,31, N 9.07%.

Found: C 66.71, H 6.18, N 8.90%.

Example 33

3-ethyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -but-2-ynyl] -1,3-dihydro-2H-indol-2-one monooxal Rate

The title compound was prepared according to Method D by applying purification method 2 starting from 2- [4-bromobut-2-ynyl) -piperazin-1-yl) -pyrimidine dihydrochloride.

M.p .: 147-149 ° C.

IR (KBr): 1714 (C = 0), 1644, 1227, 754 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.4 (1H, s), 9.8 (2H, br s), 8.36 (2H, d, J = 4.8 Hz), 7.23 (1H, d, J = 7.1 Hz), 6.93 (1H, dt, J = 1.2, 7.6 Hz), 6.84 (1H, dt, J = 0.9, 7.4 Hz), 6.67 (1H, d, J = 7.8 Hz), 6.64 (1H, t , J = 4.8 Hz), 3.69 (4H, br s), 3.44 (2H, s), 2.70, 2.51 (2x1H, d, J = 16.4 Hz), 2.44 (4H, m), 1.80-1.60 (2H, m ), 0.45 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 179.8, 163.2, 142.7, 131.5, 127.3, 123.6, 121.7, 110.8, 109.4, 109.4, 83.8, 73.4, 52.4, 50.0, 45.7, 41.7, 29.3, 26.7, 8.7 ppm.

Analysis for Formula C ₂₄ H ₂₇ N ₅ 0 ₅ (465.51):

Calc .: C 61.92, H 5.85, N 15.04%.

Found: C 61.17, H 5.84, N 14.86%.

Example 34

3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -but-2-ynyl} -1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method D by applying Purification Method 1 starting from 1- (4-bromobut-2-ynyl) -4- (2-methoxy-phenyl) -piperazine dihydrochloride.

M.p .: 161-163 ° C.

l R (KBr): 3077, 1715 (C = 0) cm ⁻¹ .

¹ H-NMR (CDCl ₃ , TMB, 400 MHz): 9.19 (1H, s), 7.21 (1H, d, J = 6.9 Hz), 7.11 (1H, dt, J = 1.2, 7.7 Hz), 7.08-6.90 (5H, m), 6.65 (1H, d, J = 7.5 Hz), 3.96 (3H, s), 3.29 (1H, d, J = 16.2 Hz), 3.17 (1H, dt, J = 2.3, 16.7 Hz) , 3.15 (2H, br s), 2.91 (2H br s), 2.78 (1H, dt, J = 2.3, 16.2 Hz), 2.65 (2H, d, J = 16.7 Hz), 2.60 (2H, br s), 2.45 (2H, broad singlet), 2.00-1.80 (2H, m), 0.68 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.6, 152.0, 141.9, 141.3, 131.7, 127.7, 123.3, 123.0, 122.3, 121.2, 118.7, 111.1, 109.7, 81.3, 75.6, 55.0, 53.4, 50.6, 50.2, 46.7, 29.7, 27.7, 8.7 ppm.

Formula C ₂₅ H ₂₉ N ₃ 0 ₂ (403.53):

Calc .: C 74.41, H 7.24, N 10.41%.

Found: C 73.43, H 7.36, N 10.19%.

Example 35

3- {4- [4- (3-Chlorophenyl) -piperazin-1-yl] -but-2-ynyl} -3-ethyl-1,3-dihydro-2H indol-2-one mono-hydro Chloride

Ethyl- (3-ethyl-2-oxo-2,3-dihydroindole) -1-carboxylate was prepared according to methods known in the literature. Sodium hydride (1.59 g; 50% suspension; 33 mmoles) was washed three times with 10 ml of hexane each and suspended in 30 ml of DMF. The reaction mixture is cooled to −20 ° C. and a solution of ethyl- (3-ethyl-2-oxo-2,3-dihydro-indole) -1-carboxylate (2.32 g; 10 mmoles) in 10 ml of DMF. Was added dropwise here at the same temperature. When hydrogen formation ceased, a solution of 1- (4-chlorobut-2-ynyl) -4- (3-chlorophenyl) -piperazine dihydrochloride (3.56 g; 10 mmoles) in 20 ml of DMF − It was added dropwise at 20 ° C. The mixture was stirred for 5 hours and 5 ml of water was added dropwise thereto to decompose excess sodium hydride and extracted with water and diethyl ether. The organic phase was dried over sodium sulphate, clarified with bone char, filtered and evaporated. The remaining pale yellow oil was dissolved in 100 ml of ethyl acetate and 1 molar equivalent of hydrogen chloride solution in 20 ml of ethyl acetate was added dropwise thereto under stirring. The isolated off-white salt was filtered off, washed with ethyl acetate and hexanes and recrystallized from isopropanol. Yield: 1.06 g white powder (24%).

M.p .: 201-203 ℃

IR (KBr): 3166, 1712 (C = 0), 760 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.96 (1H, s), 7.22 (1H, t, J = 8.1 Hz), 7.16 (1H, d, J = 7.0 Hz), 7.10-6.85 (6H , m), 4.0-2.57 (11H, m), 2.82 (1H, d, J = 16.4 Hz), 2.68 (1H, d, J = 16.4 Hz), 1.91 (1H, m), 1.80 (1H, m) , 0.65 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.4, 150.6, 141.9, 135.0, 131.0, 130.3, 127.9, 122.8, 122.3, 120.9, 116.7, 114.7, 110.6, 87.9, 68.5, 53.3, 49.5, 45.7, 29.7, 27.4, 8.7 ppm.

Assay for formula C ₂₄ H ₂₇ Cl ₂ N ₃ O (444.41):

Calc. For C 64.87, H 6.12, Cl 15.96, N 9.46%.

Found: C 64.82, H 6.11, Cl 15.94, N 9.43%.

Example 36

(Z) -3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -but-2-enyl} -3-ethyl-1,3-dihydro-2H-indole-2 -One monohydrochloride

3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -but-2-ynyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monohydro Chloride (7.15 g; 16 mmoles) was suspended in 150 ml of THF and Raney-nickel (1.0 g) was added thereto. The autoclave was hydrogenated at a temperature of 90 ° C. under a starting pressure of 10 bar. The product was then dissolved in methanol, the catalyst was filtered off and the filtrate was evaporated. The hydrochloride salt of the (Z) configuration compound containing a double bond was separated in the form of an off-white substance. Yield: 3.49 g off-white powder (49%).

M.p .: 219-222 ℃

IR (KBr): 3116, 2569, 1699 (C = 0) cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 11.4 (1H, broad s), 10.5 (1H, s), 7.29 (1H, d, J = 47.9 Hz), 7.25 (1H, d, J = 8.1 Hz), 7.18 (1H, t, J = 7.4 Hz), 7.03 (1H, s), 6.99 (1H, t, J = 7.4 Hz), 6.94 (1H, dd, J = 1.8, 8.4 Hz), 6.86 (2H, d, J = 7.5 Hz), 5.58 (1H, m), 5.43 (1H, m), 3.84 (2H, br s), 3.71 (2H, br s), 3.30 (2H, br s), 3.00 (2H, br s), 2.65, 2.55 (2x1H, dd, J = 7.3, 142 Hz), 1.80 (2H, m), 052 (3H, t, J = 7.3 Hz) ppm .

¹³ C NMR (DMSO-d ₆ , TMS, 101 MHz): 180.2, 150.8, 142.4, 134.0, 133.1, 131.4, 130.7, 127.3, 123.5, 121.5, 121.5, 120.9, 119.2, 115.3, 109.4, 52, 9, 51.3 , 49.7, 44.9, 34.6, 29.6, 8.5 ppm.

Anal for Formula C ₂₄ H ₂₉ Cl ₂ N ₃ O (446.42):

Calc. For C 64.57, H 6.55, Cl 15.88, N 9.41%.

Found: C 64.11, H 6.95, Cl 15.65, N 9.27%.

Method E (Preparation of ω-haloalkyl compound)

In a flask washed with argon, 2.5 M n-butyl lithium (60 ml; 0.15 mole) was weighed. 200 ml of THF was added thereto and the solution was cooled to -78 ° C in acetone-dried ice bath. At this temperature, a solution of 3-alkyl oxindole (0.20 mole) in 250 ml of THF was added dropwise under stirring. The mixture is stirred for an additional 10 minutes and dihaloalkanes (1-bromo-4-chlorobutane, 1-bromo-3-chloropropane, 1,5-dibromopentane or 1,6-dibromo Hexanes; 0.50 mole) was added dropwise and the solution was allowed to warm to room temperature. This was then stirred for an additional 3 hours and 20 ml of ethanol was added dropwise to decompose the excess butyl lithium. The solution was distilled off on a rotary evaporator and the remaining oil was extracted with water and ethyl acetate. The organic phase was dried over sodium sulfate. The remaining oil was triturated with hexanes to give a crystal stock. The isolated off-white crystals were stirred in 200 ml of hexane to remove excess dihaloalkanes, filtered and washed with hexanes. The product was used for the next reaction without recrystallization. Recrystallization from the indicated solvents may yield analytical samples.

Example 37

3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.

M.p .: 104-105 ° C. (hexane-ethyl acetate),

IR (KBr): 3181, 2941, 1700, 1306, 755 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.57 (br s, 1 H, NH), 7.21 (dt, 1 H, J = 7.6, 1.5 Hz, H-6), 7.12 (d, 1 H, J = 7.4 Hz, H-4), 7.06 (dt, 1H, J = 7.5, 1.0 Hz, H-5), 6.92 (d, 1H, J = 7.7 Hz, H-7), 3.39 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.96-1.84 (m, 2H, CH ₂ ), 1.83-1.74 (m, 2H, CH ₂ ), 1.74-1.60 (m, 2H, CH ₂ ), 1.24-1.18 (m, 1H), 1.08-1.03 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.4, 141.2, 132.3, 127.7, 123, 0, 122.5, 109.6, 54.1, 44.4, 36.8, 32.7, 31.0, 21.8, 8.5 ppm.

Anal for Formula C ₁₄ H ₁₈ ClNO (251.76):

Calc. For C 66.79, H 7.21, N 5.56, Cl 14.08%.

Found: C 66.89, H 7.16, N 5.84, Cl 14.19%.

Example 38

3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.

M.p .: 96-97 ° C. (hexane-ethyl acetate).

IR (KBr): 3159, 1716, 817 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.99 (br s, 1H, NH), 6.95-6.85 (m, 3H), 3.40 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.97 -1.88 (m, 2H, CH ₂ ), 1.83-1.75 (m, 2H, CH ₂ ), 1.73-1.62 (m, 2H), 1.25-1.20 (m, 1H), 1.09-1.04 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.5, 159.3 (d, J = 240.7 Hz), 137.2, 134.1 (d, J = 7.6 Hz), 114.1 (d, J = 23.7 Hz), 111.9 ( d, J = 24.4 Hz), 110.2 (d, J = 2.0 Hz), 54.8 (d, J = 2.0 Hz), 44.4, 36.8, 32.5, 31.0, 21.7, 8.4 ppm.

Anal for Formula C ₁₄ H ₁₇ ClFNO (269.75):

Calc. For C 62.34, H 6.35, N 5.19, Cl 13.14%.

Found: C 62.49, H 6.20, N 4.98, Cl 13.48%.

Example 39

3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.

Mp: 95-97 ° C. (hexane-ethyl acetate).

IR (KBr): 3195, 1728, 1132 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.34 (br s, 1 H, NH), 7.05 (dd, 1 H, J = 8.1, 5.3 Hz, H-4), 6.75 (ddd, 1H, J = 9.6, 8.1, 2.4 Hz, H-5), 6.71 (dd, 1H, J = 8.8, 2.4 Hz, H-7), 3.44 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 2.00-1.70 ( m, 4H, 2 x CH ₂ ), 1.70-1.60 (m, 2H, CH ₂ ), 1.23-1.18 (m, 1H), 1.08-1.04 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz , CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 183.3, 162.5 (d, J = 244.1 Hz), 142.5 (d, J = 7.8 Hz), 127.5 (d, J = 13.0 Hz), 123.8 (d, J = 9.5 Hz), 108.8 (d, J = 22.5 Hz), 98.5 (d, J = 27.4 Hz), 53.8, 44.4, 36.8, 32.5, 31.0, 21.6, 8.4 ppm.

Anal for Formula C ₁₄ H ₁₇ ClFN0 (269.75):

Calc. For C 62.34, H 6.35, N 5.19, Cl 13.14%.

Found: C 62.09, H 6.22, N 5.28, Cl 13.43%.

Example 40

3- (4-chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.

M.p .: 79-80 ° C. (Hexane).

IR (KBr): 3286, 1719 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.70 (br s, 1H, NH), 7.00 (d, 1H, J = 7.8 Hz, H-6), 6.92 (s, 1H, H-4) , 6.81 (d, 1H, J = 7.9 Hz, H-7), 3.39 (t, 2H, J = 6.8 Hz, CH ₂ Cl), 1.95-1.85 (m, 2H), 1.82-1.70 (m, 2H) , 1.70-1.58 (m, 2H), 1.30- 1.12 (m, 1H), 1.10-0.98 (m, 1H), 0.63 (t, 3H, J = 7.3 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.5, 138.8, 132.4, 131.9, 128.0, 123.7, 109.3, 54.1, 44.4, 36.9, 32.7, 31.0, 21.8, 8.4 ppm.

Anal for Formula C ₁₅ H ₂₀ ClNO (265.79):

Calc. For C 67.79, H 7.58, N 5.27, Cl 13.34%.

Found: C 67.98, H 7.43, N 5.11, Cl 13.09%.

Example 41

3- (4-chlorobutyl) -3-ethyl-7-methyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.

M.p .: 112-113 ° C. (hexane-ethyl acetate).

IR (KBr): 3181, 1703 (C = O), 748 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 1.07-1.02 (1H, m), 1.25-1.17 (1H, m), 1.70-1.60 (2H, m), 1.81-1.72 (2H, m), 1.96-1.86 (2H, m), 2.31 (3H, s), 3.36 (2H, t, J = 6.8 Hz), 6.94 (1H, dd, J = 1.7, 7.3 Hz), 6.97 (1H, t, J = 7.3 Hz), 7.03 (1H, dd, J = 1.4, 7,2 Hz), 9.4 (1H, br s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 16.5, 21.8, 31.0, 32.7, 36.8, 44.4, 54.4, 119.1, 120.3, 122.4, 129.1, 131.9, 140.1, 183.1 ppm.

Anal for Formula C ₁₅ H _{2 O} ClN0 (265.79):

Calc. For C 67.79, H 7.58, N 5.27, Cl 13.34%.

Found: C 67.56, H 7.49, N 5.24, Cl 13.29%.

Example 42

3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1-bromo-3-chloropropane.

M.p .: 91-93 ° C. (hexanes).

IR (KBr): 3183, 1701, 751 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.15 (hr s, 1H, NH), 7.23 (dt, 1H, J = 7.7, 1.3 Hz, H-6), 7.14 (d, 1H, J = 6.8 Hz, H-4), 7.06 (dt, 1H, J = 7.4, 0.9 Hz, H-5), 6.95 (d, 1H, J = 7.7 Hz, H-7), 3.48-3.36 (m, 2H, CH ₂ Cl), 2.02-1.93 (m, 3H), 1.85-1.78 (m, 1H), 1.66-1.54 (m, 1H), 1.44-1.30 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 141.3, 132.0, 127.9, 123.0, 122.6, 109.8, 53.7, 44.8, 34,8, 31.0, 27.5, 8.5 ppm.

Anal for Formula C ₁₃ H ₁₆ ClNO (237.73):

Calculated: C 65.68, H 6.78, N 5.89, Cl 14.91%.

Found: C 65.51, H 6.70, N 5.82, Cl 14.68%.

Example 43

3- (5-bromopentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.

M.p .: 77-78 ° C. (hexanes).

IR (KBr): 3290, 1718, 772 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.11 (br s, 1 H, NH), 7.20 (dt, 1 H, J = 7.6, 1.4 Hz, H-6), 7.11 (d, 1H, J = 7.3 Hz, H-4), 7.05 (dt, 1H, J = 7.4, 1.0 Hz, H-5), 6.94 (d, 1H, J = 7.4 Hz), 3.27 (t, 2H, J = 6.9 Hz, CH ₂ Br), 1.98-1.86 (m, 2H, CH ₂ ), 1.84-1.74 (m, 2H, CH ₂ ), 1.71 (quintet, 2H, J = 7.2 Hz, CH ₂ ), 1.38-1.24 (m, 2H ), 1.18-1.04 (m, 1H), 0.96-0.84 (m, 1H), 0.63 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.9, 141.4, 132.5, 127.6, 122.9, 122.4, 109.7, 54.2, 37.4, 33.6, 32.4, 31.0, 28.2, 23.4, 8.5 ppm.

Anal for Formula C ₁₅ H ₂₀ BrNO (310.24):

Calc. For C 58.07, H 6.50, N 4.51, Br 25.76%.

Found: C 57.95, H 6.42, N 4.67, Br 25.58%.

Example 44

3- (4-chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-isobutyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.

M.p .: 124-125 ° C. (hexane-ethyl acetate).

IR (KBr): 3208, 1713, 747 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.02 (br s, 1 H, NH), 7.21 (dt, 1 H, J = 7.5, 1.4 Hz, H-6), 7.11 (td, 1H, J = 7.4, 0.6 Hz, H-4), 7.04 (dt, 1H, J = 7.4, 1.0 Hz, H-5), 6.95 (d, 1H, J = 7.7 Hz, H-7), 3.37 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.95-1.70 (m, 4H, 2 x CH ₂ ), 1.70-1.58 (m, 2H, CH ₂ ), 1.38-1.30 (m, 1H), 1.23-1.17 (m, 1H), 1.02 -0.98 (m, 1H), 0.73 (d, 3H, J = 6.6 Hz, CH ₃ ), 0.61 (d, 3H, J = 6.6 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 183.1, 141.1, 132.6, 127.7, 123.3, 122.3, 109.8, 53.0, 46.3, 44.4, 39.2, 32.6, 25.3, 24.2, 23.6, 21.1 ppm.

Chemical Formula C ₁₆ H ₂₂ ClNO Analysis for (279.81):

Calc. For C 68.68, H 7.93, N 5.01, Cl 12.67%.

Found: C 68.49, H 7.89, N 4.92, Cl 12.89%.

Example 45

3- (5-bromopentyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.

Mp: 82-83 ° C. (hexanes). IR (KBr): 3293, 1720, 1690, 1175, 817 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.96 (br s, 1 H, NH), 6.92 (dt, 1 H, J = 8.8, 2.6 Hz, H-6), 6.86 (dd, 1H, J = 8.0, 2.6 Hz, H-4), 6.82 (dd, 1H, J = 8.4, 4.3 Hz, H-7), 3.30 (t, 2H, J = 6.9 Hz, CH ₂ Br), 1.96-1.87 (m, 2H, CH ₂ ), 1.80-1.68 (m, 4H, 2 x CH ₂ ), 1.40-1.25 (m, 2H, CH ₂ ), 1.18-1.04 (m, 1H), 0.96-0.84 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 181.8, 159.3 (d, J = 240.7 Hz), 136.9, 134.4 (d, J = 8.0 Hz), 114.0 (d, J = 23.3 Hz), 111.0 ( d, J = 24.4 Hz), 109.9 (d, J = 8,0 Hz), 54.7, 37.5, 33.6, 32.4, 31.1, 28.2, 23.5, 8.5 ppm.

Anal for Formula C ₁₅ H ₁₉ BrFNO (328.23):

Calc .: C 54.89, H 5.83, N 4.27, Br 24.34%.

Found: C 54.68, H 5.89, N 4.35, Br 24.16%.

Example 46

3- (5-bromopentyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.

M.p .: 72-73 ° C. (hexanes).

IR (KBr): 3262, 1726, 1694, 812 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 7.55 (br s, 1 H, NH), 7.00 (d, 1 H, J = 7.9 Hz, H-6), 6.92 (s, 1H, 11-4) , 6.75 (d, 1H, J = 7.8 Hz, H-7), 3.30 (t, 2H, J = 6.8 Hz, CH ₂ Br), 1.94-1.84 (m, 2H, CH ₂ ), 1.79-1.68 (m , 4H, 2 x CH ₂ ), 1.35-1.24 (m, 2H, CH ₂ ), 1.24-1.13 (m, 1H), 0.93-0.84 (m, 1H), 0.63 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 181.8, 159.3 (d, J = 240.7 Hz), 136.9, 134.4 (d, J = 8.0 Hz), 114.0 (d, J = 23.3 Hz), 111.0 ( d, J = 24.4 Hz), 109,9 (d, J = 8.0 Hz), 54.7, 37.5, 33.6, 32.4, 31.1, 28.2, 23.5, 8.5 ppm.

Anal for Formula C ₁₆ H ₂₂ BrNO (324.26):

Calc. For C 59.27, H 6.84, N 4.32, Br 24.64%.

Found: C 59.18, H 6.92, N 4.55, Br 24.51%.

Example 47

3- (5-Bromopentyl) -3-ethyl-6-fluoro-1, 3-dihydro-2H-indol-2-one

The title compound was prepared according to Method E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.

Mp: 95-96 ° C. (hexanes).

IR (KBr): 3300, 1722, 857 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.24 (br s, 1 H, NH), 7.01 (dd, 1 H, J = 8.1, 5.3 Hz, H-5), 6.72 (ddd, 1H, J = 9.6, 8.2, 2.3 Hz, H-5), 6.68 (d, 1H, J = 8.8, 2.3 Hz, H-7), 3.26 (t, 2H, J = 7.4 Hz, CH ₂ Br), 1.92-1.83 ( m, 2H, CH ₂ ), 1.80-1.65 (m, 4H, 2 x CH ₂ ), 1.35-1.25 (m, 2H, CH ₂ ), 1.09-1.00 (m, 1H), 0.92-0.84 (m, 1H ), 0.60 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 183.3, 162.4 (d, J = 244.1 Hz), 142.5 (d, J = 11.8 Hz), 127.7 (d, J = 3.1 Hz), 123.8 (d, J = 9.9 Hz), 108.7 (d, J = 22.1 Hz), 98.4 (d, J = 27.1 Hz), 53.9, 37.4, 33.6, 32.3, 31.0, 28.2, 23.4, 8.4 ppm.

Anal for Formula C ₁₅ H ₁₉ BrFNO (328.23):

Calculated: C 54.89, H 5.83, N 4.27, Br 24.34,

Found: C 54.69, H 5.67, N 4.39, Br 24.19%.

Method F (chlorination of ω-haloalkyl compound at position 5)

The haloalkyl compound (5 mmoles) is dissolved in 15 ml of glacial acetic acid, the solution is cooled until the glacial acetic acid begins to separate (14-16 ° C.), and a solution of 0.5 ml (5.7 mmoles) of sulfuryl chloride in 5 ml of glacial acetic acid Was added dropwise here. The mixture was stirred at the same temperature for 2 hours and then pipetted over ice water. The separated white material was filtered off, washed with water and hexanes, dried and used for coupling reaction without purification. Recrystallization from the indicated solvents may yield analytical samples.

Example 48

5-chloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method F starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one.

M.p .: 116-117 ° C. (hexane-ethyl acetate).

IR (KBr): 3285, 1717, 818 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.72 (br s, 1H, NH), 7.15 (dd, 1H, J = 8.2, 2.1 Hz, H-6), 7.12 (d, 1H, J = 2.1 Hz, H-4), 6.86 (d, 1H, J = 8.2 Hz, H-7), 3.41 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 2.00-1.86 (m, 2H, CH ₂ ), 1.84-1.74 (m, 2H, CH ₂ ), 1.74-1.60 (m, 2H), 1.29-1.15 (m, 1H), 1.12-0.95 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.0, 139.8, 134.2, 127.9, 127.8, 123.4, 110.7, 54.5, 44.4, 36.8, 32.5, 31.0, 21.7, 8.5 ppm.

Anal for Formula C ₁₄ H ₁₇ Cl ₂ NO (286.20):

Calc .: C 58.75, H 5.99, N 4.89, Cl 24.77%.

Found: C 58.61, H 5.96, N 4.80, Cl 24.66%.

Example 49

5-chloro-3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method F starting from 3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one.

Mp: 105-107 ° C. (hexanes). IR (KBr): 3221, 2963, 1700 (C = O), 1677, 1474 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.15 (br s, 1 H, NH), 7.21 (dd, 1 H, J = 8.2, 2.1 Hz, H-6), 7.12 (d, 1H, J = 2.0 Hz, H-4), 6.88 (d, 1H, J = 8.2 Hz, H-7), 3.43-3.39 (m, 2H, CH ₂ Cl), 2.10-1.77 (m, 4H, 2 x CH ₂ ) , 1.62-1.55 (m, 1H), 1.42-1.38 (m, 1H), 0.66 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.1, 139.8, 133.9, 128.1, 128.0, 123.5, 110.8, 54.1, 44.6, 34.7, 30.9, 27.5, 8.5 ppm.

Anal for Formula C ₁₃ H ₁₅ Cl ₂ NO (272.18):

Calc. For C 57.37, H 5.56, N 5.15, Cl 26.05%.

Found: C 57.19, H 5.64, N 5.28, Cl 25.88%.

Example 50

5-chloro-3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method F starting from 6-fluoro-3- (4-chloro-butyl) -3-ethyl-1,3-dihydro-2H indol-2-one.

M.p .: 131-133 ° C. (hexane-ethyl acetate).

IR (KBr): 3289, 1720, 1143 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.90 (br s, 1H, NH), 7.12 (d, 1H, J = 7.1, H-4), 6.79 (d, 1H, J = 8.8 Hz, H-7), 3.42 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.96-1.84 (m, 2H, CH ₂ ), 1.80-1.63 (m, 4H, 2 x CH ₂ ), 1.30-1.20 (m, 1H), 1.20-1.04 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 157.6 (d, J = 247.2 Hz), 140.9 (d, J = 11.1 Hz), 128.8 (d, J = 3.8 Hz), 124.8, 114.3 (d, J = 18.3 Hz), 99.5 (d, J = 26.7 Hz), 54.2, 44.3 , 36.8, 32.4, 31.0, 21.6, 8.4 ppm.

Anal for Formula C ₁₄ H ₁₆ Cl ₂ FNO (304.19):

Calc .: C 55.28, H 5.30, N 4.60, Cl 23.31%.

Found: C 55.19, H 5.27, N 4.58, Cl 23.34%.

Method G (5,7-dichlorination of ω-chloroalkyl compound)

Chloroalkyl compound (40 mmoles) was dissolved in 80 ml of glacial acetic acid and 9.6 ml (120 mmoles) of sulfuryl chloride was added dropwise at room temperature. The solution was kept at 60 ° C. for 3 hours. It was then cooled, poured over ice and extracted with diethyl ether. The ether phase was extracted twice with 10% by volume of NaOH solution, dried over sodium hypochlorite and evaporated. The pale yellow oil thus obtained was triturated with hexane and the crystalline white material was stirred in hexane, filtered, washed with hexane, dried and used in the coupling reaction without purification. Recrystallization from the indicated solvents may yield analytical samples.

Example 51

5,7-dichloro-3- (4-chlorobutyl) -3 -ethyl-1,3-di-hydro-2H-indol-2-one

The title compound was prepared according to Method G starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one.

M.p .: 65-67 ° C. (hexanes).

IR (KBr): 3165, 2964, 1713 (C = O), 1455 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.38 (br s, 1 H, NH), 7.20 (d, 1 H, J = 1.9 Hz, H-6), 6.97 (d, 1H, J = 1.8 Hz , H-4), 3.38 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.95-1.84 (m, 2H, CH ₂ ), 1.76-1.60 (m, 4H, 2 x CH ₂ ), 1.19- 1.16 (m, 1H), 1.04-0.96 (m, 1H), 0.62 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.5, 137.7, 135.1, 128.3, 127.6, 121.9, 115.7, 55.7, 44.3, 36.8, 32.5, 31.0, 21.7, 8.5 ppm.

Anal for Formula C ₁₄ H ₁₆ Cl ₃ NO (320.65):

Calculated: C 52.44, H 5.03, N 4.37, Cl 33.17%

Found: C 52.37, H 4.97, N 4.27, Cl 33.18%.

Example 52

5,7-dichloro-3- (4-chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method G starting from 3- (4-chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one.

M.p .: 93-94 ° C. (hexanes).

IR (KBr): 3144, 1719, 1459 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.49 (br s, 1 H, NH), 7.24 (dt, 1 H, J = 1.9 Hz, H-6), 7.01 (d, 1H, J = 1.7 Hz , H-4), 3.41 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 1.91 (m, 2H, CH ₂ ), 1.67 (m, 4H, 2 x CH ₂ ), 1.34 (m, 1H) , 1.20 (m, 1H), 1.01 (m, 1H), 0.74 (d, 3H, J = 6.7 Hz, CH ₃ ), 0.66 (d, 3H, J = 6.7 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 181.0, 137.5, 135.4, 128.2, 127.6, 122.2, 115.4, 54.5, 46.3, 44.3, 39.2, 32.4, 25.3, 24.3, 23.1, 21.1 ppm.

Anal for Formula C ₁₆ H ₂₀ Cl ₃ NO (348.70):

Calc. For C 55.11, H 5.78, N 4.02, Cl 30.50%.

Found: C 55.29, H 5.67, N 4.12, Cl 30.18%.

Example 53

7-chloro-3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one

3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one (5.40 g; 20 mmoles) is dissolved in 40 ml of glacial acetic acid and 3.2 ml (40 mmoles) of sulfuryl chloride was added dropwise to the solution at room temperature, which was kept at 60 ° C. for 4 hours. It was then cooled, poured onto ice and extracted with diethyl ether. The ether phase was extracted twice with 10% by volume NaOH solution, dried over sodium sulfate and evaporated. The pale yellow oil thus obtained was triturated with hexane and the crystalline white material was stirred in hexane, filtered, washed with hexane, dried and used in the coupling reaction without purification. Recrystallization from a mixture of hexane and ethyl acetate may give analytical samples.

M.p .: ° C (hexane-ethyl acetate).

IR (KBr): 3184, 1709, 1080, 853 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.22 (br s, 1H, NH), 6.99 (dd, 1H, J = 7.6, 2.3 Hz), 6.81 (dd, 1H, J = 7.6, 2.3 Hz ), 3.42 (t, 2H, J = 6.7 Hz, CH ₂ Cl), 2.00-1.88 (m, 2H, CH ₂ ), 1.82-1.60 (m, 4H, 2 x CH ₂ ), 1.30-1.16 (m, 1H), 1.12-1.00 (m, 1H), 0.66 (t, 3H, J = 7.4 Hz, CH ₃ ).

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.6, 158.8 (d, J = 244.5 Hz), 135.1 (d, J = 2.3 Hz), 134.9 (d, J = 8.4 Hz), 114.8 (d, J = 26.3 Hz), 114.8 (d, J = 11.0 Hz), 109.7 (d, J = 24.4 Hz), 55.8 (d, J = 1.9 Hz), 44.3, 36.8, 32.5, 31.1, 21.7, 8.5.

Anal for Formula C ₁₄ H ₁₆ Cl ₂ FNO (304.19):

Calc .: C 55.28, H 5.30, N 4.60, Cl 23.31%.

Found: C 55.19, H 5.28, N 4.65, Cl 23.19%.

Example 54

5-bromo-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one (12.59 g; 50 mmoles) is dissolved in a mixture of 100 ml dioxane and 100 ml water, A mixture of 2.84 ml bromine (55 mmoles), 11.9 g KBr (100 mmoles) and 50 ml water was added dropwise to the solution at 80-90 ° C. in 30 minutes. The reaction mixture was then held at this temperature for 30 minutes, cooled and 500 ml of water was added dropwise thereto. The product was isolated in the form of a white substance. The separated material was filtered off, washed with water and hexanes and used for coupling reaction without purification. Recrystallization from a mixture of hexane and ethyl acetate may give analytical samples.

M.p .: 117-118 ° C. (hexane-ethyl acetate).

IR (KBr): 3286, 1717, 1198, 817 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): δ 9.28 (br s, 1H, NH), 7.35 (dd, 1H, J = 8.2, 2.0 Hz, H-6), 7.24 (d, 1H, J = 2.0 Hz, H-4), 6.84 (d, 1H, J = 8.2 Hz, H-7), 3.41 (t, 2H, J = 6.8 Hz, CH ₂ Cl), 1.98-1.75 (m, 2H, CH ₂ ), 1.74-1.60 (m, 4H, 2 × CH ₂ ), 1.27-1.16 (m, 1H), 1.11-1.01 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH ₃ );

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 140.4, 134.6, 130.7, 126.1, 115.3, 111.3, 54.5, 44.3, 36.7, 32.8, 30.9, 21.7, 8.5.

Anal for Formula C ₁₄ H ₁₇ BrClNO (330.65):

Calc .: C 50.86, H 5.18, N 4.24%.

Found: C 50.79, H 5.09, N 4.38%.

Example 55

3- (4-chlorobutyl) -3-ethyl-2-oxoindolin-5-sulfonyl chloride

90 ml of chlorosulfonic acid are cooled to 0 ° C. and 3- (4-chlorobutyl) -3-ethyl-oxindole (11.34 g; 45 mmoles) is added here in portions so that the temperature does not exceed 2 ° It was not. The solution was allowed to warm to room temperature under stirring and carefully pipetted over ice after 30 minutes. The separated white precipitate was filtered off, washed with water and hexanes and used for coupling reaction without purification. Recrystallization from a mixture of hexane and ethyl acetate may give analytical samples.

M.p .: ° C.

IR (KBr): 3197, 1729, 1371, 1176 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.39 (br s, 1 H, NH), 7.99 (dd, 1 H, J = 8.4, 1.9 Hz, H-6), 7.80 (d, 1 H, J = 1.9 Hz, H-4), 7.16 (d, 1H, J = 8.4 Hz, H-7), 3.46-3.41 (m, 2H, CH ₂ Cl), 2.10-1.83 (m, 4H, 2 x CH ₂ ) , 1.73-1.66 (m, 2H), 1.32-1.18 (m, 1H), 1.14-1.00 (m, 1H), 0.68 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.4, 147.6, 138.4, 133.9, 128.8, 121.9, 110.1, 54.5, 44.2, 36.4, 32.2, 30.9, 21.5, 8.5 ppm.

Anal for Formula C ₁₄ H ₁₇ Cl ₂ NO ₃ S (350.27):

Calc .: C 48.01, H 4.89, N 4.00, Cl 20.24, S 9.15%.

Found: C 47.89, H 4.76, N 4.18, Cl 20.01, S 9.38%.

Example 56

3- (4-chlorobutyl) -3-ethyl-2-oxoindolin 5-sulfonamide

3- (4-chlorobutyl) -3-ethyl-2-oxoindolin 5-sulfonyl chloride (9.96 g; 30 mmoles) is dissolved in 450 ml of ethanol, 25% aqueous ammonia solution (9 ml, 120 mmoles) Was added dropwise to the solution at 0-2 ° C. The mixture was allowed to warm up to room temperature. It was further stirred for 1 hour, evaporated and the remaining white material was stirred in water, filtered, washed with water and hexanes and used for coupling reaction without purification. Recrystallization from a mixture of hexane and ethyl acetate may give analytical samples.

M.p .: 171-172 ° C. (ethyl acetate).

IR (KBr): 3343, 3265, 1725, 1327, 1169 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.8 (br s, 1H, NH), 7.70 (dd, 1H, J = 8.1, 1.8 Hz, H-6), 7.65 (d, 1H, J = 1.7 Hz, H-4), 6,98 (d, 1H, J = 8.1 Hz, H-7), 3.54-3.49 (m, 2H, CH ₂ Cl), 1.82-1.73 (m, 4H, 2 x CH ₂ ), 1.59 (quintet, 2H, J = 7.2 Hz, CH ₂ ), 1.15-1.00 (m, 1H), 1.00-0.85 (m, 1H), 0.52 (t, 3H, J = 7.4 Hz, CH ₃ ) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 181.0, 145.7, 137.6, 132.6, 126.6, 120.9, 109.1, 53.4, 45.1, 36.2, 32.3, 30.3, 21.5, 8.5 ppm.

Anal for Formula C ₁₄ H ₁₉ ClN ₂ O ₃ S (330.84):

Calc .: C 50.83, H 5.79, N 8.47, Cl 10.72, S 9.69%.

Found: C 50.79, H 5.74, N 8.51, Cl 10.71, S 9.72%.

Method H (coupling reaction of ω-chloroalkyl compound)

In the coupling reaction, a suitable chloroalkyl compound was coupled with a secondary amine. The melt of substrate (12 mmoles) was slowly stirred and heated to 180 ° C., and the cycloalkyl compound (12 mmoles) and sodium carbonate (1.36 g; 12 mmoles) were metered in at the same temperature. The mixture was reacted for 1 hour. The melt was then cooled, ethyl acetate and water added to it, and the phases separated. The organic phase was evaporated and the remaining oil was treated by chromatography on a single column using ethyl acetate as eluent. The desired compound was prepared as the main product of column chromatography.

Treatment Method 1 : If the product purified by column chromatography became crystalline upon trituration with diethyl ether, it was filtered and recrystallized from the indicated solvent after the melting point of the given material. The desired compound was obtained in the form of white crystals.

Treatment method 2 : If the basic product does not become crystalline upon addition of diethyl ether, it is dissolved in 200 ml of ether, a small amount of suspended precipitate is filtered off, and the calculated amount in 50 ml of diethyl ether in pure solution (1 Molar equivalents) of hydrogen chloride solution was added under vigorous stirring. The separated white salt was filtered off, washed with ether and hexanes and dried in vacuo pistol for 3 hours at room temperature. If necessary, the hydrochloride salt was recrystallized.

Treatment Method 3 : If the basic product does not crystallize upon addition of diethyl ether and does not provide a salt that can be well-filtered with hydrogen chloride, it is dissolved in 100 ml of hot ethyl acetate and in 50 ml of hot ethyl acetate One molar equivalent of oxalic acid dihydrate solution was added dropwise with stirring within 10 minutes. The white oxalate salt was separated by cooling. It was filtered at room temperature, washed with ethyl acetate and hexanes and dried.

Example 57

5-Chloro-3- {3- [4- (3-chlorophenyl) -piperazin-1-yl) -propyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was purified by 5-chloro-3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2-chloro-6,7-dihydro-4H-thieno. Prepared according to Method H by applying Treatment Method 1 starting from [3,2-c] pyridine.

M.p .: 117-119 ° C. (hexane-ethyl acetate).

IR (KBr): 3172 (NH), 1718 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.65 (3H, t, J = 7.4 Hz), 1.28-1.04 (1H, m), 1.40-1.24 (lH, m), 1.82-1.75 (2H, m), 2.00-1.89 (2H, m), 2.27 (2H, t, J = 7.4 Hz), 2.41 (4H, t, J = 5.0 Hz), 3.12 (4H, t, J = 5.0 Hz), 6.73 ( 1H, dd, J = 2.4, 8.4 Hz), 6.78 (1H, dd, J = 1.7, 7.9 Hz), 6.82 (1H, t, J = 2.2 Hz), 6.84 (1H, d, J = 8.2 Hz), 7.10 (1H, d, J = 2.0 Hz), 7.13 (1H, t, J = 8.1 Hz), 7.19 (1H, dd, J = 2.1, 8.2 Hz) 9.17 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 152.2, 139.9, 134.9, 134.4, 129.9, 127.9, 127.7, 123.4, 119.2, 115.6, 113.7, 110.6, 58.1, 54.5, 52.9, 48.5, 35.1, 31.0, 21.6, 8.5 ppm.

Anal for Formula C ₂₃ H ₂₇ Cl ₂ N ₃ O (432.40):

Calc. For C 63.89, H 6.29, Cl 16.40, N 9.72%.

Found: C 63.50, H 6.34, Cl 16.00, N 9.69%.

Example 58

3-ethyl-3- [3- (4-pyridin-2-yl-piperazin-1-yl) -propyl] -1,3-dihydro-2H-indol-2-one

Treatment method 1 was carried out starting from 3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine. Application was made according to Method H.

M.p .: 122-124 ° C. (hexane-ethyl acetate).

IR (KBr): 3194, 1710 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 1.28-1.23 (1H, m), 1.38-1.32 (1H, m), 1.80-1.78 (2H, m), 1.97-1.81 (2H, m), 2.26 (2H, t, J = 7.5 Hz), 2.40 (4H, t, J = 4.7 Hz), 3.49-3.44 (4H, m), 6.61-6.57 (2H , m), 6.90 (1H, d, J = 7.7 Hz), 7.04 (1H, dt, J = 1.0, 7.5 Hz), 7.12 (1H, d, J = 6.4 Hz), 7.19 (1H, dt, J = 1.3, 7.7 Hz), 7.44 (1H, dt, J = 2.0, 7.9 Hz), 8.16 (1H, doublet of doublets, J = 1.9, 5.6 Hz), 9.02 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 159.5, 147.8, 141.4, 137.3, 132.4, 127.6, 122.9, 122.3, 113.1, 109.6, 106.9, 58.4, 54.0, 52.9, 45.0, 35.2, 31.0, 21.5, 8.5 ppm.

Assay for Compound C ₂₂ H ₂₈ N ₄ O (364.49):

Calc .: C 72.50, H 7.74, N 15.37%.

Found: C 72.23, H 7.69, N 15.28%.

Example 59

5-Bromo-3-ethyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

Title compound starts from 5-bromo-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 114-115 ° C. (hexane-ethyl acetate).

IR (KBr): 3096, 1731 (C = O), 812 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 9.15 (1H, broad singlet), 8.17 (1H, dd, J = 1.6, 5.3 Hz), 7.46 (1H, dt, J = 2.0, 7.8 Hz), 7.32 (1H, dd, J = 1.9, 8.2 Hz), 7.22 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J = 8.2 Hz), 6.64-6.60 (2H, m), 3.56 (4H , br s), 2.54 (4H, br s), 2.33 (2H, br s), 1.96-1.86 (2H, m), 1.79-1.71 (2H, m), 1.58-1.38 (2H, m), 1.18- 1.03 (1H, m), 0.98-0.85 (1H, m), 0.63 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.9, 159.2, 149.5, 147.9, 139.5, 137.5, 134.8, 126.1, 115.1, 113.4, 111.1, 107.1, 57.9, 54.5, 52.7, 44.7, 37.3, 31.0, 26.3, 22.1, 8.5 ppm.

Anal for Formula C ₂₃ H ₂₉ BrN ₄ O (457.42):

Calc .: C 60.39, H 6.39, Br 17.47, N 12.25%.

Found: C 59.90, H 6.38, Br 17.24, N 11.98%.

Example 60

3- {4- [4- (3-Chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol- ₂ -one-H ₂ O-HCl Isopropanol (1: 1: 1: 1)

Apply the treatment method 2 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-di-hydro-2H indol-2-one and 1- (3-chlorophenyl) -piperazine Was prepared according to Method H.

M.p .: 109-111 ° C.

IR (KBr): 1701 (C = O), 1180 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 11.14 (1H, broad s), 10.44 (1H, s), 7.25 (1H, t, J = 8.2 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.18 (1H, dt, J = 1.2, 7.7 Hz), 7.03 (1H, t, J = 2.1 Hz), 6.99 (1H, dt, J = 0.9, 7.6 Hz), 6.94 (1H, dd , J = 1.9, 8.3 Hz), 6.86 (1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 7.9 Hz), 4.37 (1H, br s), 3.84 (2H, br s), 3.83 -3.75 (1H, m), 3.5-3.3 (4H, br s), 3.21 (2H, t), 3.10-2.85 (4H, br s), 1.85-1.65 (4H, m), 1.65-1.55 (2H, m), 1.04 (2H, d, J = 6.1 Hz), 1.01-0.94 (1H, m), 0.9-0.7 (1H, m), 0.51 (3H, t, J = 7.3 Hz) ppm.

^I3 C-NMR (DMSO-d ₆ , TMS, 101 MHz): 180.8, 151.0, 142.7, 134.1, 132.1, 130.8, 127.8, 123.2, 121.8, 119.3, 115.4, 114.3, 109.4, 62.2, 55.1, 53.2, 50.3, 44.9, 36.6, 30.3, 25.7, 23.2, 21.4, 8.6 ppm.

Anal for Formula C ₂₇ H ₄₁ Cl ₂ N ₃ 0 ₃ (526.55):

Calc. For C 61.59, H 7.85, Cl 13.47, N 7.98%.

Found: C 61.88, H 7,58, Cl 13.68, N 8.05%.

Example 61

5-Bromo-3- {4- [4- (3-chlorophenyl) piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monooxal Rate

Title compound starts from 5-bromo-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-phenyl) -piperazine Was prepared according to Method H by applying Treatment Method 3.

M.p .: 200-202 ° C.

IR (KBr): 3200, 1706 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.5 (1H, s), kb. 7.8 (2H, br S), 7.45 (1H, d, J = 2.0 Hz), 7.35 (1H, dd, J = 1.8, 8.2 Hz), 7.23 (1H, t, J = 8.1 Hz), 7.00 (1H, t, J = 2.1 Hz), 6.92 (dd, J = 2.2, 8.0 Hz), 6.83 (1H, dd, J = 1.8, 8.2 Hz), 6.81 (1H, d, J = 8.2 Hz), 3.36 (4H, br s), 3.04 (4H, br s), 2.80 (2H, t, J = 8.1 Hz), 1.85-1.66 (4H, m), 1.54-1.48 (2H, m), 0.97-0.89 (1H, m) , 0.84-0.77 (1H, m), 0.50 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 180.4, 164.2, 151.9, 142.0, 134.1, 134.0, 130.7, 130.5, 126.2, 119.1, 115.2, 114.2, 113.7, 111.3, 55.0, 53.6, 50.9, 45.6, 36.5, 30.2, 23.9, 21.5, 8.5 ppm.

Anal for Formula C ₂₆ H ₃₁ BrClN ₃ O ₅ (580.91):

Calc. For C 53.76, H 5.38, N 7.23%.

Found: C 53.89, H 5.60, N 7.11%.

Example 62

3-isobutyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

Treatment method 1 was carried out starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine. Application was made according to Method H.

M.p .: 158-159 ° C. (hexane-ethyl acetate).

IR (KBr): 3192, 1719 (C = 0) cm ^-1 .

^OneH-NMR (CDCl₃, TMS, 400 MHz): 9.03 (1H, s), 8.17 (1H, ddd, J = 1.0, 1.9, 4.8 Hz), 7.44 (1H, dt, J = 2.0 7.9 Hz), 7.19 (1H, dt, J = 1.3, 7.6 Hz), 7.10 (1H, d, J = 6.8 Hz), 7.03 (1H, dt, J = 0.9, 7.4 Hz), 6.90 (1H, d, J = 7.7 Hz ), 6.60 (1H, dd, J = 0.7.7.4 Hz), 6.60 (dt, J = 0.7, 7.0 Hz), 3.48 (4H, t, J = 5.2 Hz), 2.44 (4H, t, J = 5.1 Hz ), 2.21 (2H, t, J = 7.8 Hz), 1.86-1.82 (2H, m), 1.80-1.66 (2H, m), 1.50-1.28 (3H, m), 1.16-1.14 (1H, m), 0.92.0.80 (1H, m), 0.69 (3H, d, J = 6.7 Hz), 0.58 (3H, d, J = 6.7 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 183.2, 159.5, 147.9, 141.2, 137.3, 132.0, 127.5, 123.3, 122.2, 113.2, 109.6, 107.0, 58.3, 53.1, 52.9, 46.3, 45.1, 39.9, 26.8, 25.3, 24.2, 23.1, 21.6 ppm.

Chemical Formula C ₂₅ H ₃₄ N ₄ 0 Analysis for (406.58):

Calc .: C 73.86, H 8.43, N 13.78%.

Found: C 73.39, H 8.34, N 13.50%.

Example 63

3- {4- [4- (2,3-Dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl) -3-ethyl-1,3-dihydro -2H-indole-2-one

The title compound was purified by 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 4- (2,3-dihydrobenzo [1,4] dioxine-5 Prepared according to Method H by applying Treatment Method 1 starting from -yl) -piperazine.

M.p .: 169-170 ° C. (hexane-ethyl acetate).

IR (KBr): 3025, 1710 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.3 Hz), 0.92-0.89 (1H, m), 1.13-1.09 (1H, m), 1.49-1.42 (2H, m), 1.82-1.74 (2H, m), 1.95-1.87 (2H, m), 2.30 (2H, t, J = 7.9 Hz), 2.61 (4H, br s), 3.07 (4H, br s), 4.24 -4.21 (2H, m), 4.31-4.27 (4H, m), 6.50 (1H, dd, J = 1.4, 8.0 Hz), 6.58 (1H, dd, J = 1.4, 8.2 Hz), 6.75 (1H, 1H , t, J = 8.1 Hz), 6.89 (1H, d, J = 7.7 Hz), 7.04 (1H, dt, J = 0.9, 7.4 Hz), 7.11 (1H, d, J = 6.7 Hz), 7.19 (1H , dt, J = 1.3, 7.6 Hz), 8.80 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.4, 144.0, 141.5, 141.4, 136.4, 132.5, 127.6, 123.0, 122.3, 120.6, 111.9, 110.7, 109.5, 64.3, 63.9, 58.2, 54.1, 53.1, 50.3, 37.5, 31.0, 26.6, 22.2, 8.5 ppm.

Anal for Formula C ₂₆ H ₃₃ N ₃ O ₃ (435.57):

Calculated: C 71.70, H 7.64, N 9.65%.

Found: C 71.50, H 7.60, N 9.60%.

Example 64

3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] -butyl) -3-isobutyl-1,3-dihydro -2H-indole-2-one

The title compound was converted to 3- (4-chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one and 4- (2,3-dihydro-benzo [1,4] dioxine Prepared according to Method H by applying Treatment Method 1 starting from -5-day) -piperazine.

M.p .: 152-154 ° C. (hexane-ethyl acetate).

IR (KBr): 3331, 3081, 1706 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.61 (3H, d, J = 6.7 Hz), 0.72 (3H, d, J = 6.7 Hz), 0.89-0.83 (1H, m), 1.11-1.06 (1H, m), 1.33 (1H, m), 1.47-1.38 (2H, m), 1.79-1.67 (2H, m), 1.93-1.84 (2H, m), 2.29 (2H, t, J = 7.9 Hz ), 2.61 (4H, br s), 3.07 (4H, br s), 4.24-4.21 (2H, m), 4.31-4.27 (4H, m), 6.51 (1H, dd, J = 1.4, 8.1 Hz), 6.58 (1H, dd, J = 1.4, 8.2 Hz), 6.75 (1H, 1H, t, J = 8.2 Hz), 6.89 (1H, d, J = 7.7 Hz), 7.03 (1H, dt, J = 0.8, 7.4 Hz), 7.10 (1H, d, J = 6.9 Hz), 7.19 (1H, dt, J = 1.3, 7.6 Hz), 8.88 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.9, 144.0, 141.5, 141.2, 136.4, 132.8, 127.5, 123.3, 122.2, 120.6, 111.9, 110.7, 109.6, 64.3, 63.9, 58.2, 53.1, 53.0, 50.3, 46.3, 39.9, 26.6, 25.3, 24.2, 23.1, 21.6 ppm.

Chemical Formula C ₂₈ H ₃₇ N ₃ O ₃ Analysis for (463.63):

Calc. For C 72.54, H 8.04, N 9.06%.

Found: C 72.53, H 8.00, N 9.02%.

Example 65

5,7-dichloro-3-ethyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

The title compound was obtained from 5,7-dichloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Prepared according to Method H by starting Treatment Method 1.

M.p .: 144-146 ° C. (hexane-ethyl acetate).

IR (KBr): 3081, 1737 (C = O), 772 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.65 (3H, t, J = 7.4 Hz), 0.98-0.86 (1H, m), 1.18-1.04 (1H _, m), 1.48-1.38 (2H , m), 1.80-1.70 (2H, m), 2.00-1.90 (2H, m), 2.26 (2H, t, J = 7.7 Hz), 2.48 (4H, t, J = 5.1 Hz), 3.50 (4H, t, J = 5.1 Hz), 6.62-6.58 (2H, m), 7.00 (1H, d, J = 1.9 Hz), 7.22 (1H, d, J = 1.9 Hz), 7.45 (1H, dt, J = 2.0, 7.9 Hz), 8.17 (1H, ddd, J = 0.9, 1.9., 4.9 Hz), 8.79 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.8, 159.5, 147.9, 137.9, 137.3, 135.4, 128.0, 127.5, 121.9, 115.1, 113.2, 107.0, 58.0, 55.6, 52.9, 45.0, 37.4, 31.0, 26.6, 22.2, 8.5 ppm.

Anal for Formula C ₂₃ H ₂₈ Cl ₂ N ₄ 0 (447.41):

Calc. For C 61.75, H 6.31, Cl 15.85, N 12.52%.

Found: C 62.14, H 6.34, Cl 15.74, N 12.21%.

Example 66

5-Chloro-3-ethyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

The title compound is derived from 5-chloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 154-156 ° C. (hexane-ethyl acetate).

IR (KBr): 3157, 1729 (C = O), 1597, 775 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 40 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.98-0.85 (1H, m), 1.18-1.04 (1H, m), 1.53-1.35 (2H, m), 1.83-1.70 (2H, m), 1.96-1.86 (2H, m), 2.25 (2H, t, J = 7.6 Hz), 2.47 (4H, t, J = 5.1 Hz), 3.49 (4H, t , J = 5.1 Hz), 6.62-6.58 (2H, m), 6.83 (1H, d, J = 8.2 Hz), 7.09 (1H, d, J = 2.1 Hz), 7.17 (1H, dd, J = 2.1, 8.2 Hz), 7.45 (1H, dt, J = 2.0, 7.9 Hz), 8.17 (lH, dm, J = 4.7 Hz), 9.13 (1H, s) ppm.

^f3 C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 159.5, 147.9, 140.0, 137.4, 134.5, 127.7, 127.6, 123.4, 113.2, 110.5, 107.0, 58.1, 54.6, 52.9, 45.1, 37.4, 31.0, 26.8, 22.2, 8.5 ppm.

Anal for Formula C ₂₃ H ₂₉ ClN ₄ 0 (412.97):

Calc. For C 66.90, H 7.08, Cl 8.58, N 13.57%.

Found: C 66.22, H 7.04, Cl 8.33, N 13.27%.

Example 67

5-Chloro-3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was purified by 5-chloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H-thieno [3,2. -c] Prepared according to Method H by applying Treatment Method 1 starting from pyridine.

M.p .: 139-142 ° C. (hexane-ethyl acetate).

lR (KBr): 3412, 1712 (C = O), 780 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 0.95-0.88 (1H, m), 1.13-1.07 (1H, m), 1.45-1.36 (2H, m), 1.80-1.71 (2H, m), 1.96-1.88 (2H, m), 2.24 (2H, t, J = 7.5 Hz), 2.48 (4H, t, J = 5.0 Hz), 3.13 (4H, t , J = 5.0 Hz), 6.73 (1H, ddd, J = 0.5, 2.3, 8.4 Hz), 6.78 (1H, ddd, J = 0.6, 1.8, 7.8 Hz), 6.84 (1H, d, J = 8.0 Hz) , 6.84 (1H, t, J = 2.1 Hz), 7.09 (1H, d, J = 2.1 Hz), 7.13 (1H, t, J = 8.2 Hz), 7.18 (1H, dd, J = 2.1, 8.2 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.4, 152.3, 140.0, 134.8, 134.5, 129.9, 127.8, 127.6, 123.4, 119.1, 115.6, 113.7, 110.6, 57.9, 54.7, 52.9, 48.5, 37.4, 31.0, 26.8, 22.1, 8.5 ppm.

Anal for Formula C ₂₄ H ₂₉ Cl ₂ N ₃ O (446.42):

Calc. For C 64.57, H 6.55, Cl 15.88, N 9.41%.

Found: C 64.55, H 6.53, Cl 15.75, N 9.40%.

Example 68

3- [4- (4-phenylpiperazin-1-yl) -butyl] ^. -3-ethyl-1,3-dihydro-2H-indol-2-one monooxalate

The title compound is prepared according to Method H by applying Treatment Method 3 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1-phenylpiperazine It was.

M.p .: 121-123 ° C.

IR (KBr): 3245, 1710, 1620 (C = O) cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.77 (2H, br s), 10.46 (1H, s), 7.30-7.16 (4H, m), 7.02-6.91 (3H, m), 6.89 (1H, d, J = 7.7 Hz), 6.84 (1H, t, J = 7.3 Hz), 3.37 (4H, br s), 3.20 (4H, br s), 2.93, 2.90 (2H, d, J = 6.0 Hz), 2.0-1.72 (4H, m), 1.56 (2H, m), 0.98 (1H, m), 0.83 (1H, m), 0.51 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.9, 149.9, 142.7, 132.2, 129.3, 127.6, 123.2, 121.8, 120.1, 116.1, 109.4, 55.4, 53.2, 50.8, 45.7, 36.8, 30.4, 23.5, 21.5, 8.6 ppm.

Anal for Formula C ₂₆ H ₃₃ N ₃ O ₅ (467.57):

Calc. For C 66.79, H 7.11, N 8.99%.

Found: C 65.09, H 7.21, N 8.73%.

Example 69

3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one monooxalate

Treatment method 3 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-di-hydro-2H-indol-2-one and 1- (2-methoxyphenyl) -piperazine Was prepared according to Method H.

M.p .: 180-183 ° C.

IR (KBr): 3201, 1707 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.4 (1H, br s), 9.1 (2H, br s), 7.21 (1H, d, J = 7.9 Hz), 7.18 (1H, dt, J = 7.7, 1.1 Hz), 7.02-6.94 (3H, m), 6.91-6.87 (2H, m), 6.86 (1H, d, J = 7.7 Hz), 3.78 (3H, s), 3.15 (8H, br s), 2.88 (2H, t, J = 7.8 Hz), 1.78-1.68 (4H, m), 1.53 (2H, m), 0.99-0.94 (1H, m), 0.83-0.77 (1H, m), 0.51 (3H, t, J = 7.3 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 180.8, 164.6, 152.0, 142.7 139.8 132.2 127.8, 123.5, 123.2, 121.7, 121.0, 118.4, 112.1, 109.3, 55.5, 55.5, 53.2, 51.4, 47.4 , 36.6, 30.4, 23.7, 21.5, 8.6 ppm.

Analysis for Formula C ₂₇ H ₃₅ N ₃ 0 ₆ (497.60):

Calc. For C 65.17, H 7.09, N 8.44%.

Found: C 65.10, H 7.07, N 8.46%.

Example 70

3-ethyl-3- [4- (4-pyrimidin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one monooxalate

Treatment method 3 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 4- (pyrimidin-2-yl) -piperazine Was prepared according to Method H.

M.p .: 132-134 ° C.

IR (KBr): 3200, 1700, 1622, 1198 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 10.4 (1H, s), 8.42 (2H, d, J = 4.8 Hz), 8.4 (2H, br s), 7.20 (1H, d, J = 7.7 Hz), 7.17 (1H, dt, J = 1.1, 7,6 Hz), 6.99 (1H, dt, J = 0.8, 7.5 Hz), 6.86 (1H, d, J = 7.7 Hz), 3.92 (4H , br s), 3.05 (4H, br s), 2.82 (2H, t, J = 8.0 Hz), 1.79-1.67 (4H, m), 1.53 (2H, m), 0.98-0.95 (1H, m), 0.82-0.78 (1H, m), 0.50 (3H, t, J = 7.4 Hz) ppm,

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 180.9, 164.5, 142.7, 132.2, 127.8, 123.2, 121.7, 109.4, 55.7, 53.2, 50.8, 40.9, 36.6, 30.4, 23.8, 21.5, 8.6 ppm .

Anal for Formula C ₂₄ H ₃₁ N ₅ O ₅ (469.55):

Calc. For C 61.39, H 6.65, N 14.92%.

Found: C 61.38, H 6.61, N 14.84%.

Example 71

3-ethyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

Treatment method 1 was carried out starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine. Application was made according to Method H.

M.p .: 131-133 ° C. (hexane-ethyl acetate).

IR (KBr): 3237, 1720 (C = O), 1691 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.88 (1H, s), 8.17 (1H, doublet of doublets, J = 1.9, 5.4 Hz), 7.46 (1H, dt, J = 2.0, 7.9 Hz), 7.19 (1H, dt, J = 1.4, 7.6 Hz), 7.11 (1H, d, J = 7.4 Hz), 7.04 (1H, dt, J = 0.9, 7.4 Hz), 6.91 (1H, d, J = 7.7 Hz) , 6.62 (1H, d, J = 7.2 Hz), 6.61 (1H, d, J = 7.9 Hz), 3.56 (4H, t, J = 4.2 Hz), 2.55 (4H, br s), 2.31 (2H, t, J = 7.8 Hz), 1.97-1.87 (2H, m), 1.83-1.74 (2H, m), 1.53-1.44 (2H, m), 1.14-1.08 (1H, m), 0.95-0.89 (lH, m), 0.63 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.5, 159.3, 147.9, 141.4, 137.4, 132.4, 127.6, 123.0, 122.3, 113.4, 109.6, 107.0, 58.1, 54.1, 52.7, 44.7, 37.4, 31.0, 26.4, 22.2, 8.5 ppm.

Analysis for Formula C ₂₃ H ₃₀ N ₄ 0 (378.52):

Calc .: C 72.98, H 7.99, N 14.80%.

Found: C 72.66, H 8.01, N 14.67%.

Example 72

3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one 5-sulfonamide monooxal Rate

Method H was applied by treatment method 3 starting from 3- (4-chlorobutyl) -3-ethyl-2-oxo-indolin 5-sulfonamide and 2- (pyridin-1-yl) -piperazine. It was prepared according to.

M.p .: 188-190 ° C.

IR (KBr): 3352, 1720 (C = O), 1319, 1161 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.53 (3H, t, J = 7.4 Hz), 0.90-0.76 (1H, m), 1.04-0.90 (1H, m), 1.60-1.46 ( 2H, m), 1.86-1.70 (4H, m), 2.82 (2H, t, J = 7.8 Hz), 3.06 (4H, br s), 3.37 (4H, br s), 6.84 (1H, dd, J = 1.2, 7.8 Hz), 6.92 (1H, dd, J = 1.8, 8.4 Hz), 7.00 (1H, t, J = 2.1 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.24 (lH, t, J = 8.1 Hz), 7.67 (1H, d, J = 1.7 Hz), 7.70 (1H, dd, J = 1.8, 8.2 Hz), 8.0-6.8 (4H, br s), 10.84 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 181.0, 164.3, 151.3, 145.8, 137.6, 134.1, 132.5, 130.7, 126.6, 120.9, 119.1, 115.3, 114.2, 109.2, 55.6, 53.4, 50.9, 45.5, 36.4, 30.2, 23.9, 21.5, 8.5 ppm.

Anal for Formula C ₂₆ H ₃₃ ClN ₄ 0 ₇ S (581.09):

Calc. For C 53.74, H 5.72, Cl 6.10, N 9.64, S 5.52%.

Found: C 53.38, H 5.67, Cl 6.06, N 9.41, S 5.33%.

Example 73

3- {4- {4- (4-Chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1- (4-chloro-phenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 175-177 ° C. (ethyl acetate).

IR (KBr): 3171, 1712 (C = O), 815 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), 0.90-0.85 (1H, m), 1.20-0.90 (1H, m), 1.50-1.30 (2H, m), 1.94-1.73 (4H, m), 2.24 (2H, t, J = 7.8 Hz), 2.34 (3H, s), 2.49 (4H, t, J = 5.0 Hz), 3.10 (4H, t, J = 5.0 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.79 (2H, d, J = 9.1 Hz), 6.92 (1H, d, J = 0.6 Hz), 6.99 (1H, d, J = 7.9 Hz), 7.18 (2H, doublet, J = 9.1 Hz), 8.45 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.8, 149.8, 139.0, 132.6, 131.6, 128.8, 127.8, 124.3, 123.6, 117.0, 109.2, 58.1, 54.2, 52.9, 48.9, 37.5, 31.0, 26.9, 22.2, 21.2, 8.5 ppm.

Anal for Formula C ₂₅ H ₃₂ ClN ₃ O (426.01):

Calc. For C 70.49, H 7.57, Cl 8.32, N 9.86%.

Found: C 70.16, H 7.34, Cl 8.16, N 9.61%.

Example 74

3-ethyl-3- {4- [4- (4-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one

Treating method 1 was carried out starting with 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-methoxyphenyl) -piperazine. Application was made according to Method H.

M.p .: 109-110 ° C. (hexane-ethyl acetate).

IR (KBr): 3172, 1713 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.96-0.86 (1H, m), 1.18-1.06 (1H, m), 1.49-1.34 (2H, m), 1.84-1.74 (2H, m), 1.97-1,88 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.51 (4H, t, J = 4.9 Hz), 3.04 (4H , t, J = 4.9 Hz), 3.76 (3H, s), 6.91-6.79 (5H, m), 7.05 (1H, dt, J = 0.9, 7.4 Hz), 7.12 (1H, dd, J = 0.6, 7.4 Hz), 7.20 (1H, dt, J = 1.4, 7.7 Hz), 8.23 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.2, 153.7, 145.7, 141.2, 132.6, 127.6, 123.1, 122.4, 118.1, 114.4, 109.4, 58.3, 55.5, 54.1, 53.2, 50.5, 37.6, 31.1, 27.0, 22.3, 8.5 ppm.

Anal for Formula C ₂₅ H ₃₃ N ₃ 0 ₂ (407.56):

Calculated: C 73.68, H 8.16, N 10.31%.

Found: C 72.89, H 8.27, N 10.14%.

Example 75

3- (4- {4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-isobutyl-1,3-dihydro-2H indol-2-one monohydro-chloride

Treatment method 2 was carried out starting from 3- (4-chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) -piperazine. Application was made according to Method H.

M.p .: 214-216 ° C.

IR (KBr): 3166, 2411, 1701 (C = 0) cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.56 (3H, d, J = 6.7 Hz), 0.67 (3H, d, J = 6.7 Hz), 0.79-0.72 (1H, m), 1.03 -0.91 (1H, m), 1.25-1.15 (1H, m), 1.80-1.55 (6H, m), 2.94 (4H, br s), 3.18 (2H, t, J = 11.9 Hz), 3.44-3.35 ( 4H, m), 6.86 (1H, d, J = 7.9 Hz), 6.86 (1H, dd, J = 2.0, 7.8 Hz), 6.93 (1H, dd, J = 1.9, 8.4 Hz), 6.98 (1H, dt , J = 0.9, 7.5 Hz), 7.03 (1H, t, J = 2.1 Hz), 7.17 (1H, dt, J = 1.2, 7.7 Hz), 7.22 (1H, d, J = 7.7 Hz), 7.25 (1H , t, J = 8.1 Hz), 10.4 (1H, s), 11.1 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 181.2, 151.0, 142.4, 134.1, 132.4, 130.8, 127.7, 123.5, 121.6, 119.3, 115.4, 114,3, 109.4, 55.0, 52.1, 50.3, 45.7, 44.9, 38.9, 25.7, 25.1, 24.2, 23.2, 20.8 ppm.

Anal for Formula C ₂₅ H ₃₅ Cl ₂ N ₃ O (476.49):

Calc. For C 65.54, H 7.40, Cl 14.88, N 8.82%.

Found: C 65.05, H 7.35, Cl 14.45, N 8.65%.

Example 76

3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

Apply Treatment Method 1 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Was prepared according to Method H.

M.p .: 145-146 ° C. (hexane-ethyl acetate).

IR (KBr): 3163, 1712 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.98-0.84 (1H, m), 1.18-1.06 (1H, m), 1.50-1.36 (2H, m), 1.96-1.73 (4H, m), 2,24 (2H, t, J = 7.8 Hz), 2.49 (4H, t, J = 5.0 Hz), 3.10 (4H, t, J = 5.0 Hz), 6.80 (2H, d, J = 9.0 Hz), 6.88 (1H, dt, J = 0.7, 7.7 Hz), 7.05 (1H, dt, J = 1.0, 7.5 Hz), 7.12 (1H, dt, J = 0.7, 7.4 Hz), 7.18 (2H, d, J = 9.2 Hz), 7.20 (1H, dt, J = 1.4, 7.6 Hz), 7.92 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 149.9, 141.3, 132.6, 128.9, 127.6, 124.4, 123.0, 122.3, 117.1, 109.5, 58.1, 54.2, 52.9, 49,0, 37.5, 31.0, 26.9, 22.2, 8.5 ppm.

Anal for Formula C ₂₄ H ₃₀ ClN ₃ O (411.98):

Calculated: C 69.97, H 7.34, Cl 8.61, N 10.20%.

Found: C 69.49, H 7.37, Cl 8.63, N 10.06%.

Example 77

3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl) -3-ethyl-6-fluoro-1,3-dihydro-2H indol-2-one

Title compound starts from 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-phenyl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 116-117 ° C. (hexane-ethyl acetate).

IR (KBr): 3163, 1717 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), 0.98-0.84 (1H, m), 1.16-1.04 (1H, m), 1.50-1.34 (2H, m), 1.80-1.72 (2H, m), 1.95-1.87 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.48 (4H, t, J = 5.0 Hz), 3.13 (4H, t , J = 5.0 Hz), 6.67 (1H, dd, J = 2.3, 8.8 Hz), 6.76-6.70 (2H, m), 6.78 (1H, ddd, 0.8, 1.9, 8.0 Hz), 6.83 (1H, t, J = 2.1 Hz), 7.03 (1H, dd, J = 5.4, 8.1 Hz), 7.13 (1H, t, J = 8.0 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 22.2, 26.8, 31.0, 37.5, 48.5, 52.9, 53.9, 58.1, 98.3 (d, J = 26.7 Hz), 108.6 (d, J = 22.1 Hz ), 113.7, 115.6, 119.1, 123.8 (d, J = 9.5 Hz), 127.8 (d, J = 3.1 Hz), 129.9, 134.8, 142.6 (d, J = 11.8 Hz), 152.2, 162.4 (d, J = 244.1 Hz) ppm.

Anal for Formula C ₂₄ H ₂₉ ClFN ₃ O (429.97):

Calculated: ^C. 67.04, H 6.80, Cl 8.25, N 9.77%.

Found: ^C. 66.97, H 6.86, Cl 8.18, N 9.74%.

Example 78

3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one

Treatment of the title compound starting from 3- (4-chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) -piperazine Prepared according to Method H by applying Method 1.

M.p .: 142-144 ° C. (hexane-ethyl acetate).

IR (KBr): 3178, 1714 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.98-0.86 (1H, m), 1.16-1.04 (1H, m), 1.32-1.50 (2H, m), 1.80-1.70 (2H, m), 1.96-1.86 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.34 (3H, s), 2.48 (4H, t, J = 5.0 Hz ), 3.13 (4H, t, J = 5.0 Hz), 6.74 (1H, dd, J = 2.1, 8.3 Hz), 6.78 (1H, dd, J = 2,5, 7.9 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.84 (1H, t, J = 2.1 Hz), 6.92 (1H, s), 6.99 (1H, d, J = 7.8 Hz), 7.13 (1H, t, J = 8.1 Hz), 8.26 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 152.3, 138.8, 134.9, 132.6, 131.8, 129.9, 127.9, 123.8, 119.1, 115.6, 113.7, 109.1, 58.1, 54.2, 52.9, 48.5, 37.6, 31.1, 26.9, 22.3, 21.2, 8.6 ppm.

Anal for Formula C ₂₅ H ₃₂ ClN ₃ 0 (426.01):

Calc. For C 70.49, H 7.57, Cl 8.32, N 9.86%.

Found: C 70.37, H 7.56, Cl 8.26, N 9.79%.

Example 79

5,7-dichloro-3- [4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl] -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was obtained from 5,7-dichloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-phenyl) -piperazine. Prepared according to Method H by starting Treatment Method 1.

M.p .: 182-183 ° C. (ethanol)

] R (KBr): 3100, 1732 (C = 0), 744 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.52 (3H, t, J = 7.3 Hz), 0.88-0.75 (1H, m), 0.98-0.90 (1H, m), 1.40-1.20 ( 2H, m), 1.85-1.70 (4H, m), 2.20-2.09 (2H, m), 2.37 (4H, t, J = 4.6 Hz), 3.09 (4H, t, J = 4.6 Hz), 6.76 (1H, dd, J = 1.3, 7.8 Z), 6.85 (1H, dd, J = 1.8, 8.3 Hz), 6.89 (1H, t, J = 2.0 Hz), 7-19 (1H, t , J = 8.1 Hz), 7.36 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 1.9 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 180.5, 152.4, 139.5, 136.0, 133.9, 130.4, 127.2, 126.4, 122.4, 118.0, 114.5, 114.1, 113.6, 57.2, 55.0, 52.5, 47.7, 36.7, 30.4, 26.2, 21.8, 8.5 ppm.

Anal for Formula C ₂₄ H ₂₈ Cl ₃ N ₃ 0 (480.87):

Calculation: C 59.95, H 5.87, Cl 22.12, N 8.74%.

Found: C 59.86, H 5.94, Cl 21.43, N 8.58%.

Example 80

3-ethyl-5-methyl-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 168-170 ° C. (ethyl acetate-ethanol).

IR (KBr): 1717 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.62 (3H, t), 0.92-0.60 (1H, m), 1.26-1.09 (1H, m), 1.50-1.37 (2H, m), 1.79- 1.71 (2H, m), 1.95-1.85 (2H, m), 2.23 (2H, t, J = 7.8 Hz), 2.45 (4H, t, J = 5.1 Hz), 3.48 (4H, t, J = 5.1 Hz ), 6.59 (1H, m), 6.60 (1H, d, J = 7.8 Hz), 6.78 (1H, d, J = 79 Hz), 6.92 (1H, s), 6.98 (1H, dd, J = 0.9, 7.9 Hz), 7.45 (1H, dt, J = 2.0, 7.7 Hz), 8.18-8.16 (1H, m), 8.77 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 159.5, 147.9, 138.9, 137.4, 132.6, 131.7, 127.9, 123.7, 113.1, 109.2, 107.0, 58.3, 54.2, 52.9, 45.1, 37.6, 31.0, 26.9, 22.3, 21.2, 8.5 ppm.

Chemical Formula C ₂₄ H ₃₂ N ₄ 0 Analysis for (392.55):

Calc. For C 73.43, H 8.22, N 14.27%.

Found: C 73.11, H 8.19, N 14.26%.

Example 81

3- {4- [4- (2-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

Apply Treatment Method 1 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (2-chlorophenyl) -piperazine Was prepared according to Method H.

M.p .: 145-148 ° C. (hexane-ethyl acetate).

IR (KBr): 3178, 1705 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 0.93-0.86 (1H, m), 1.20-1.15 (1H, m), 1.52-1.34 (2H, m), 1.84-1.74 (2H, m), 1.98-1.86 (2H, m), 2.27 (2H, t, J = 7.8 Hz), 2.55 (4H, br s), 3.03 (4H, br s), 6.91 (1H, d ,, J = 7.7 Hz), 6.94 (1H, dt, J = 1.5, 7.6 Hz), 7.01 (1H, dd, J = 1.5, 8.1 Hz),, 7.05 (1H, dt, J = 1.0, 7.5 Hz), 7.12 (1H, dd, J = 1.2, 7.3 Hz), 7.23-7.17 (2H, m), 7.33 (1H, doublet of doublets, J = 1.5, 7.6 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.4, 149.3, 141.3, 132.6, 130.6, 128.7, 127.6, 127.5, 123.5, 123.0, 122.3, 120.3, 109.5, 58.2, 54.2, 53.2, 51.1, 37.6, 31.0, 27.0, 22.3, 8.5 ppm.

Anal for Formula C ₂₄ H ₃₀ ClN ₃ 0 (411.98):

Calculation: C 69.97, H 7.34, Cl 8.61, N 10.20%.

Found: C 69.88, H 7.36, Cl 8.90, N 9.89%.

Example 82

3-ethyl-6-fluoro- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

Title compound starts from 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 137-139 ° C. (hexane-ethyl acetate).

IR (KBr): 3150, 1712 (C = O), 1141 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.3 Hz), 0.96-0.85 (1H, m), 1.16-1.14 (1H, m), 1.52-1.34 (1H, m), 1.82-1.72 (2H, m), 1.98-1.86 (2H, m), 2.25 (2H, t, J = 7.8 Hz), 2.47 (4H, t, J = 5.0 Hz), 3.50 (4H, t , J = 5.0 Hz), 6.65-6.61 (2H, m), 6.66 (1H, dd, J = 2.2, 8.8 Hz), 6.75 (1H, dt, J = 2.2, 8.9 Hz), 7.05 (1H, dd, J = 5.4, 8.1 Hz), 7.47 (1H, dt, J = 1.9, 7.8 Hz), 8.20-8.18 (1H, m), 8.79 (1H, br s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 22.2, 26.9, 31.0, 37.6, 45.1, 52.9, 53.8, 58.3, 98.2 (d, J = 27.1 Hz), 107.0, 108.6 (d, J = 22.5 Hz), 113.2, 123.9 (d, J = 9.6 Hz), 127.8 (d, J 2.7 Hz), 137.4, 142.5 (d, J = 11.4 Hz), 147.9, 159.5, 162.4 (d, J = 244.1 Hz) , 182.8 ppm.

Chemical Formula C ₂₃ H ₂₉ FN ₄ O Analysis for (396.51):

Calc. For C 69.67, H 7.37, N 14.13%.

Found: C 69.04, H 7.40, N 13.93%.

Example 83

3- {4- [4- (2,3-Dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl} -3-ethyl-6-fluoro-1 , 3-dihydro-2H-indol-2-one

The title compound was prepared as 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one and 4- (2,3-dihydro-benzo [1, 4] Prepared according to Method H by applying Treatment Method 1 starting from dioxin-5-yl) -piperazine.

M.p .: 146-147 ° C. (hexane-ethyl acetate).

IR (KBr): 1714 (C = 0), 1000 mc ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), 10.95-0.84 (1H, m), 1.16-1.04 (1H, m), 1.50-1.32 (2H, m), 2.00-1.70 (4H, m), 2.26 (2H, t, J = 7.8 Hz), 2.56 (4H, br s), 3.00 (4H, br s), 4.31-4.21 (4H, m), 6.51 (1H, dd, J = 1.5, 8.0 Hz), 6.58 (1H, dd, J = 1.4, 8.2 Hz), 6.63 (1H, dd, J = 2.3, 8.8 Hz), 6.78-6.70 (2H, m), 7.03 (1H, dd, J = 5.3 , 8.2 Hz), 8.89 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.7, 22.5, 27.1, 31.3, 37.8, 50.9, 53.4, 54.0, 58.5, 64.2, 64.5, 98.4 (d, J = 27.5 Hz), 108.8 (d, J = 22.2 Hz), 110.9, 112.1, 120.8, 124.1 (d, J = 9.5 Hz), 128.1 d, J = 2.7 Hz), 136.6, 141.9, 142.8 (d, J = 11.8 Hz), 144.2, 162.5 (d , J = 244.1 Hz), 183.0 ppm.

Analysis for formula C ₂₆ H ₃₂ FN ₃ O ₃ (453.56):

Calculated: C 68.85, H 7.11, N 9.26%.

Found: C 68.76, H 7.07, N 9.30%.

Example 84

3-ethyl-5-fluoro-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

Title compound starts from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 144-147 ° C. (hexane-ethyl acetate).

IR (KBr): 1710, 1592, 1486 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 8.73 (1H, broad s), 8.17 (1H, m), 7.45 (1H, m), 6.87 (3H, m), 6.61 (1H, m), 6.60 (1H, m), 3.49 (4H, t, J = 5.1 Hz), 2.46 (4H, t, J = 5.1 Hz), 2.24 (2H, t, J = 7.6 Hz), 1.93 (2H, m), 1.76 (2H, m), 1.43 (2H, m), 1.12 (1H, m), 0.91 (1H, m), 0.64 (3H, t, J = 7.4 Hz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.3, 159.5, 159.2 (d, J = 240.3 Hz), 147.9, 137.4, 137.2 (d, J = 1.9 Hz), 134.5 (d, J = 7.6 Hz ), 114.0 (d, J = 23.3 Hz), 113.2, 110.9 (d, J = 24.0 Hz), 110.0 (d, J = 8.0 Hz), 107.0, 58.2, 54.9 (d, J = 1.9 Hz), 53.0, 45.1, 37.5, 31.0, 26.8, 22.2, 8.5 ppm.

Anal for Formula C ₂₃ H ₂₉ FN ₄ 0 (396.51):

Calc. For C 69.67, H 7.37, N 14.13%.

Found: C 69.15, H 7.30, N 14.09%.

Example 85

3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one mono- Hydrochloride

The title compound was obtained from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-phenyl) -piperazine. Prepared according to Method H by starting Treatment Method 2.

M.p .: 121-124 ° C.

IR (KBr): 1711 (C = O), 1178 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.3 Hz), 0.82-0.76 (1H, m), 1.00-0.92 (1H, m), 1.83-1.61 ( 6H, m), 2.96 (4H, br s), 3.17 (2H, br s), 3.41 (2H, br s), 3.80 (2H, br s), 6.87-6.83 (2H, m), 6.94 (1H, dd, J = 2.1, 8.3 Hz), 6.99 (1H, dd, J = 8.5 Hz), 7.03 (lH, t, J = 2.0 Hz), 7.18 (H, dd, J = 2.7, 8.5 Hz), 7.24 ( 1H, t, J = 8.1 Hz) 10.5 (1H, s), 11.0 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.5, 21.4, 23.2, 30.2, 36.5, 44.9, 50.4, 53.9, 54.0, 55.1, 110.0 (d, J = 8.0 Hz), 111.2 (d, J = 24.0 Hz), 114.0 (d, J = 23.3 Hz), 114.3, 115.4, 119.3, 130.8, 134.1, 134.2 (d, J = 8.0 Hz), 138.8 (d, J = 1.5 Hz), 151.0, 158.3 ( d, J = 236.5 Hz), 180.6 ppm.

Assay for Formula C ₂₄ H ₃₀ Cl ₂ FN ₃ O (466.43):

Calc. For C 61.80, H 6.48, Cl 15.20, N 9.01%.

Found: C 60.57, H 6.50, Cl 14.70, N 8.77%.

Example 86

3- {4- [4- (4-Chlorophenyl) -piperazin-1-yl] -butyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 145-147 ° C. (hexane-ethyl acetate).

IR (KBr): 3284, 1716 (C = O), 1088 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.96-0.84 (1H, m), 1.12-1.04 (1H, m), 1.48-1.35 (2H, m), 1.80-1.71 (2H, m), 1.95-1.81 (2H, m), 2.25 (2H, t, J = 7.8 Hz), 2.50 (4H, t, J = 5.0 Hz), 3.11 (4H, t , J = 5.0 Hz), 6.64 (1H, dd, J = 2.4, 8.7 Hz), 6.75 (1H, ddd, J = 2.4, 8.2, 9.7 Hz), 6.81 (2H, d, J = 9.0 Hz), 7.04 (1H, dd, J = 5.3, 8.2 Hz), 7.18 (2H, d, J = 8.9 Hz), 8.28 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 22.2, 26.9, 31.1, 37.6, 49.0, 53.0, 53.8, 58.1, 98.2 (d, J = 27.1 Hz), 108.7 (d, J = 22.1 Hz ), 117.1, 123.9 (d, J = 9.9 Hz), 124.4, 127.8 (d, J = 2.7 Hz), 128.9, 142.4 (d, J = 11.4 Hz), 149.9, 162.4 (d, J = 244.2 Hz), 182.6 ppm.

Anal for Formula C ₂₄ H ₂₉ ClFN ₃ O (429.97):

Calc. For C 67.04, H 6.80, Cl 8.25, N 9.77%.

Found: C 66.81, H 6.79, Cl 8.10, N 9.70%.

Example 87

5,7-dichloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was obtained from 5,7-dichloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-chloro-phenyl) -piperazine. Prepared according to Method H by starting Treatment Method 2.

M.p .: 152-154 ° C. (heptane-ethyl acetate).

IR (KBr): 3137, 1719 (C = O), 826 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.65 (3H, t, J = 7.4 Hz), 0.98-0.86 (1H, m), 1.16-1.04 (1H, m), 1.50-1.36 (2H, m), 1.80-1.70 (2H, m), 1.98-1.88 (2H, m), 2.27 (2H, t, J = 7.8 Hz), 2.51 (4H, t, J = 5.0 Hz), 3.12 (4H, t , J = 5.0 Hz), 6.81 (2H, d, J = 9.1 Hz), 7.01 (1H, d, J = 1.8 Hz), 7.18 (2H, d, J = 9.1 Hz), 7.23 (1H, d, J = 1.8 Hz), 8.15 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.3, 149.9, 137.7, 135.3, 128.9, 128.2, 127.5, 124.4, 122.0, 117.1, 115.7, 57.9, 55.8, 53.0, 49.1, 37.5, 31.1, 26.7, 22.2, 8.5 ppm.

Anal for Formula C ₂₄ H ₂₈ Cl ₃ N ₃ 0 (480.87):

Calc. For C 59.95, H 5.87, Cl 22.12, N 8.74%.

Found: C 59.80, H 5.86, Cl 21.83, N 8.72%.

Example 88

7-chloro-3- {4- [4- (3-chlorophenyl) -piperazin-1-yl) -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indole- 2-one monohydrochloride

The title compound was diluted with 7-chloro-3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) piperazine. Prepared according to Method H by applying Treatment Method 2 starting from.

M.p .: 205-207 ° C.

IR (KBr): 3127, 3088, 1713 (C = O), 779 cm ^-1 .

¹ H-NMR (DMSO-d ₅ , TMS, 400 MHz): 0.53 (3H, t, J = 7.3 Hz), 0.83-0.78 (1H, m), 0.99-0.93 (1H, m), 1.88-1.64 ( 6H, m), 2.98 (4H, br s), 3.21 (2H, t, J = 11.5 Hz), 3.43 (2H, br s), 3.84 (2H, d, J = 11.7 Hz), 6.86 (1H, dd , J = 1.5, 7.8 Hz), 6.94 (1H, dd, J = 2.0, 8.1 Hz), 7.03 (1H, t, J = 2.0 Hz), 10.9 (1H, s), 11.3 (1H, br s) ppm .

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 21.4, 23.2, 30.0, 36.5, 44.9, 50.3, 55.0, 110.5 (d, J = 24.4 Hz), 113.5 (d, J = 11.1 Hz), 114.3, 114.7 (d, J = 26.7 Hz), 115.4, 119.3, 130.8, 134.1, 135.4 (d, J = 8.4 Hz), 136.8 (d, J = 2.3 Hz), 151, 0, 158.0 (d, J = 240.7 Hz), 180.5 ppm.

Anal for Formula C ₂₄ H ₂₉ Cl ₃ FN ₃ 0 (500.88):

Calc. For C 57.55, H 5.84, Cl 21.23, N 8.39%.

Found: C 56.80, H 5.77, Cl 20.93, N 8.33%.

Example 89

5-Chloro-3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-6-fluoro-1,3-dihydro-2H-indole- 2-one monohydrochloride

The title compound was purified by 5-chloro-3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) -pipe Prepared according to Method H by applying Treatment Method 2 starting from Razine.

M.p .: 237-239 ° C.

IR (KBr): 3133, 2446, 1710 (C = O), 1150, 946 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.3 Hz), 0.96-0.78 (2H, in), 1.87-1.63 (6H, m), 2.98 (4H, s), 3.20 (2H, t, J = 11.8 Hz), 3.48-3.42 (2H, m), 3.83 (2H, d, J = 12.5 Hz), 6.86 (1H, dd, J = 1.4, 7.8 Hz), 6.90 (1H, d, J = 9.4 Hz), 6.94 (1H, dd, J = 2.0, 8.2 Hz), 7.03 (1H, t, J = 2.0 Hz) , 7.25 (1H, t, J = 8.2 Hz), 7.52 (1H, d, J = 7.4 Hz), 10.79 (1H, s), 11.15 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.5, 21.4, 23.2, 30.2, 36.4, 44.9, 50.3, 53.4, 55.0, 99.0 (d, J = 26.3 Hz), 111.7 (d, J = 18.3 Hz), 114.3, 115.4, 119.3, 125.1, 129.4 (d, 3.4 Hz), 130.8, 134.1, 143.0 (d, J = 11.5 Hz), 151.0, 156.9 (d, J = 243.8 Hz), 180.6 ppm.

Anal for Formula C ₂₄ H ₂₉ Cl ₃ FN ₃ 0 (500.88):

Calc. For C 57.55, H 5.84, Cl 21.23, N 8.39%.

Found: C 57.08, H 5.71, Cl 20.76, N 8.27%.

Example 90

3- {4- [4- (4-Chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 148-150 ° C. (hexane-ethyl acetate).

IR (KBr): 3278, 1716 (C = O), 1178, 823 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 0.97-0.86 (1H, m), 1.16-1.07 (1H, m), 1.49-1.35 (2H, m), 1.81-1.70 (2H, m), 1.98-1.88 (2H, m), 2.25 (2H, t, J = 7.5 Hz), 2.50 (4H, t, J = 5.0 Hz), 3.11 (4H, t, J = 5.0 Hz), 6.80 (2H, d, J = 9.1 Hz), 6.94-6.78 (3H, m), 7.18 ( 2H, d, J = 9.1 Hz), 8.03 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz); 8.5, 22.2, 26.8, 31.1, 37.5, 49.0, 53.0, 54.9 (d, J = 1.9 Hz), 58.1, 110.0 (d, J = 8.0 Hz), 111.0 (d, J = 24.4 Hz), 114.0 (d, J = 23.7 Hz), 117.1, 124.4, 128.9, 134.4 (d, J = 8.0 Hz), 137.1 (d, J = 1.9 Hz), 149.9, 159.2 (d, J = 240.3 Hz), 182.2 ppm.

Anal for Formula C ₂₄ H ₂₉ ClFN ₃ 0 (429.97):

Calc. For C 67.04, H 6.80, Cl 8.25, N 9.77%.

Found: C 66.35, H 6.78, Cl 8.11, N 9.69%.

Example 91

3-ethyl-3- {4- [4- (3-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one

Treating method 1 was carried out starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3-methoxyphenyl) -piperazine. Application was made according to Method H.

M.p .: 123-125 ° C. (hexane-ethyl acetate).

IR (KBr): 3363, 1705 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), (2H, t, J = 7.8 Hz), 2.49 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 3.76 (3H, s), 6.39 (1H, ddd , J = 0.6, 2.3, 8.1 Hz), 6.43 (1H, t, J = 2.3 Hz), 6.50 (1H, ddd, J = 0.6, 2.3, 8.2 Hz), 6.90 (1H, d, J = 7.6 Hz) , 7.03 (1H, dt, J = 1.0, 7.5 Hz), 7.10 (1H, dd, J = 0.8, 7.4 Hz), 7.14 (1H, t, J = 8.1 hH), 7.18 (1H, dt, J = 1.3 , 7.6 Hz), 9.39 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.9, 160.4, 152.6, 141.5, 132.5, 129.6, 127.5, 122.9, 122.2, 109.5, 108.7, 104.2, 102.3, 58.1, 55.0, 54.1, 52.9, 48.8, 37.4, 30.9, 26.8, 22.2, 8.5 ppm.

Anal for Formula C ₂₅ H ₃₃ N ₃ 0 ₂ (407.56):

Calculated: C 73.68, H 8.16, N 10.31%.

Found: C 73.50, H 8.19, N 10.11%.

Example 92

3- {5- [4- (3-Chlorophenyl) -piperazin-1-yl] -pentyl} -3-ethyl-1,3-dihydro-2H indol-2-one monooxalate

Apply Treatment Method 3 starting from 3- (5-bromopentyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (3-chlorophenyl) -piperazine. Was prepared according to Method H.

M.p .: 127-129 ° C.

IR (KBr): 3187, 1705 (C = O), 754 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.90-0.76 (1H, m), 1.04-0.90 (1H, m), 1.15 (2H, q, J = 6.8 Hz), 1.50 (2H, q, J = 7.5 Hz), 1.80-1.64 (4H, m) , 2.81 (2H, t, J = 7.9 Hz), 3.07 (4H, br s), 3.38 (4H, br s), 6.84 (2H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 2.0 , 8.4 Hz), 6.98 (1H, dt, J = 0.9, 7.6 Hz), 7.00 (1H, t, J = 2.3 Hz), 7.16 (1H, dt J = 1.1, 7.7 Hz), 7.20 (1H, d, J = 7.6 Hz), 7.24 (1H, dt, J = 8.1 Hz), 8.8-7.4 (2H, br s), 10.35 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 180.9, 164.3, 151.3, 142.3, 134.1, 132.4, 130.7, 127.7, 123.1, 121.6, 119.1, 115.2, 114.2, 109.3, 55.9, 53.2, 50.9, 45.6, 36.9, 30.5, 26.6, 23.8, 23.6, 8.6 ppm.

Anal for Formula C ₂₇ H ₃₄ ClN ₃ 0 ₅ (516.04):

Calc. For C 62.84, H 6.64, Cl 6.87, N 8.14%.

Found: C 62.43, H 6.68, Cl 6.92, N 8.04%.

Example 93

3-ethyl-3- [5- (4-pyridin-2-yl-piperazin-1-yl) -pentyl] -1,3-dihydro-2H-indol-2-one

Treatment method 1 starting from 3- (4-bromopentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Was prepared according to Method H.

M.p .: 127-128 ° C. (hexane-ethyl acetate).

IR (KBr): 3155, 1710 (C = 0), 1683 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.93-0.88 (1H, m), 1.30-1.09 (3H, m), 1.40-1.35 (2H, m), 1.95-1.70 (4H, m), 2.47 (4H, t, J = 5.1 Hz), 3.50 (4H, t, J = 5.0 Hz), 6.63-6.58 (2H, m), 6.90 (1H, dd , J = 0.3, 7.7 Hz), 7.04 (1H, dt, J = 1.0, 7.5 Hz), 7.11 (1H, dd, J = 0.6, 6.7 Hz), 7.18 (1H, dt, J = 1.4, 7.6 Hz) , 7.45 (1H, dt, J = 2.0, 7.8 Hz), 8.17 (1H, ddd, J = 0.8, 2.0, 4.9 Hz), 8.90 (1H, br s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 159.5, 147.9, 141.4, 137.3, 132.7, 127.5, 122.9, 122.3, 113.2, 109.5, 107.4, 58.6, 54.2, 53.0, 45.1, 37.6, 31.1, 27.7, 26.4, 24.1, 8.5 ppm.

Chemical Formula C ₂₄ H ₃₂ N ₄ 0 Analysis for (392.55):

Calc. For C 73.43, H 8.22, N 14.27%.

Found: C 72.96, H 8.19, N 14.02%.

Example 94

3- {5- [4- (2-Chlorophenyl) -piperazin-1-yl] -pentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one monohydro-chloride

Treatment method 2 was carried out starting from 3- (5-bromopentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (2-chlorophenyl) -piperazine. Application was made according to Method H.

M.p .: 100-103 ° C.

IR (KBr): 3432, 2459, 1709 (C = 0) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MMz): 0.62 (3H, t, J = 7.4 Hz), 1.0-0.90 (1H, m), 1.18-1.08 (1H, m), 1.31-1.20 (2H, m), 1.93-1.72 (6H, m), 2.91 (2H, t, J = 8.4 Hz), 3.2- 2.9 (2H, br s), 3.7-3.3 (6H, br s), 6.95 (1H, d, J = 7.8 Hz), 7.10-7.02 (3H, m), 7.11 (1H, d, J = 6.4 Hz) , 7.20 (1H, dt, J = 1.4, 7.7 Hz), 7.23 (1H, dt, J = 1.5, 7.6 Hz), 7.36 (1H, dd, J = 1.6, 7.8 Hz), 8.56 (1H, s), 12.6 (1H, broad singlet) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.0, 147.1, 141.3, 132.2, 130.6, 128.7, 127.9, 127.7, 125.1, 123.0, 122.4, 121.0, 109.7, 57.3, 53.9, 52.2, 47.9, 37.1, 31.1, 26.7, 23.7, 23.1, 8.5 ppm.

Anal for Formula C ₂₅ H ₃₃ Cl ₂ N ₃ 0 (462.47):

Calc. For C 64.93, H 7.19, Cl 15.33, N 9.09%.

Found: C 64.08, H 7.18, Cl 15.12, N 9.04%.

Example 95

3-ethyl-3- {4- [4- (4-fluorophenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H indol-2-one

Treating method 1 was carried out starting with 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-fluorophenyl) -piperazine. Application was made according to Method H.

M.p .: 118-119 ° C. (hexane-ethyl acetate).

IR (KBr): 3161, 1713 (C = O) cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.94-0.88 (1H, m), 1.14-1.10 (1H, m), 1.47-1.35 (2H, m), 1.84-1.74 (2H, m), 1.97-1.88 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.50 (4H, t, J = 4.9 Hz), 3.06 (4H, t , J = 4.9 hz), 6.82 (2H, dd, J = 4.7, 9.3 Hz), 6.90 (1H, d, J = 8.0 Hz), 6.93 (2H, t, J = 9.1 Hz), 7.04 (1H, dt , J = 0.8, 7.5 Hz), 7.11 (1H, d, J = 6.6 Hz), 7.19 (1H, dt, J = 1.3, 7.6 Hz), 9.06 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.5, 22.2, 26.9, 31.0, 37.5, 50.0, 53.1, 54.2, 58.1, 109.5, 115.4 (d, J = 22.1 Hz), 117.6 (d, J = 7.6 Hz), 122.3, 123.0, 127.6, 132.6, 141.4, 147.9 (d, J = 1.9 Hz), 157.0 (d, J = 238.8 Hz), 182.8 ppm.

Analysis for Formula C ₂₄ H ₃₀ FN ₃ O (395.52):

Calc .: C 72.88, H 7.65, N 10.62%.

Found: C 73.22, H 7.74, N 10.47%.

Example 96

3- {4- [4- (4-Chloro-3-trifluoromethyl-phenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H indole-2- Monohydrochloride

The title compound was obtained from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (4-chloro-3-trifluoroethyl-phenyl) -piperazine. Prepared according to Method H by starting Treatment Method 2.

M.p .: 204-206 ° C.

IR (KBr): 3177, 1700 (C = O), 1307, 1137 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.60 (3H, t, J = 7.4 Hz), 1.00-0.90 (1H, m), 1.16-1.04 (1H, m), 1.96-1.72 (6H, m), 3.00-2.88 (4H, m), 3.68-3.47 (6H, m), 6.97 (1H, dd, J = 2.8, 8.9 Hz), 6.98 (1H, d, J = 7.2 Hz), 7.03 (1H , t, J = 7.4 Hz), 7.08 (1H, d, J = 6.4 Hz), 7.17 (1H, d, J = 2.7 Hz), 7.19 (1H, dt, J = 1.3, 7.6 Hz), 7.37 (1H , d, J = 8.8 Hz), 9.29 (1H, s), 12.47 (1H, br s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 8.4, 21.7, 23.3, 31.1, 36.6, 46.2, 51.3, 51.4, 53.8, 56.9, 110.0, 116,0 (q, J = 5.7 Hz), 120.8, 122.4, 122.6 (q, J = 273.5 Hz), 122.8, 123.8 (q, J = 1.5 Hz), 127.8, 128.9 (q, J = 31.3 Hz), 131.7, 132.3, 141.5, 148.0, 181.9 ppm.

Anal for Formula C ₂₅ H ₃₀ Cl ₂ F ₃ N ₃ O (516.44):

Calc. For C 58.14, H 5.86, Cl 13.73, N 8.14%.

Found: C 57.99, H 5.85, Cl 13.67, N 8.07%.

Example 97

3- {4- [4- (3,4-Dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one hydrogen chloride-water Isopropanol (1: 1: 1: 1)

Treatment of the title compound starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3,4-dichloro-phenyl) -piperazine 2 was applied to prepare according to Method H.

M.p .: 224-226 ° C.

IR (KBr): 3385, 1708 (C = O), 946 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.3 Hz), 0.81-0.77 (1H, m), 1.01-0.95 (1H, m), 1.82-1.62 ( 6H, m), 3.6-2.9 (8H, m), 3.82 (1H, br s), 4.38 (1H, br s), 6.87 (1H, d, J = 7.6 Hz), 7.02-6.97 (2H, m) , 7.23-7.16 (3H, m), 7.44 (1H, d, J = 9.0 Hz), 10.4 (1H, s), 11.1 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 21.4, 23.3, 30.3, 36.6, 44.9, 50.2, 53.2, 55.1, 109.4, 116.0, 117.1, 120.9, 121.7, 123.2, 127.8, 130.8, 131.8, 132.1, 142.7, 149.5, 180.8 ppm.

Assay for formula C ₂₇ H ₄₀ Cl ₃ N ₃ 0 ₃ (561.00):

Calc .: C 57.81, H 7.19, Cl 18.96, N 7.49%.

Found: C 58.46, H 7.26, Cl 18.89, N 7.87%.

Example 98

3- {4- [4- (4-Chloro-2-methylphenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monohydrochloride

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-chloro-2-methyl-phenyl) -piperazine Treatment Method 2 was applied to prepare according to Method H.

M.p .: 247-249 ° C.

IR (KBr): 3138, 2435, 1712 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.86-0.81 (1H, m), 0.98-0.96 (1H, m), 1.76-1.63 ( 6H, m), 2.24. (3H, s), 2.97 (2H, s), 3.11 (8H, br s), 6.85 (1H, d, J = 7.7 Hz), 7.00 (1, dt, J = 1.0, 7.5 Hz), 7.04 (1H , d, J = 8.5 Hz), 7.18 (1H, dt, J = 1.2, 7.6 Hz), 7.23-7.21 (2H, m), 7.26 (1H, d, J = 2.2 Hz), 10.45 (1H, s) , 11.1 (1H, broad singlet) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 17.4, 21.4, 23.3, 30.3, 36.6, 48.1, 51.3, 53.2, 55.1, 109.4, 120.9, 121.7, 123.2, 126.5, 127.8, 130.6, 132.1, 134.7, 142.7, 148.9, 180.8 ppm.

Anal for Formula C ₂₅ H ₃₃ Cl ₂ N ₃ O (462.47):

Calc. For C 64.93, H 7.19, Cl 15.33, N 9.09%.

Found: C 65.25, H 7.27, Cl 15.00, N 9.02%.

Example 99

3- (4- [4- (3-chloro-4-methylphenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-4-methyl-phenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 103-106 ° C. (hexane-ethyl acetate).

IR (KBr): 3166, 1716 (C = O), 749 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.49 (3H, t, J = 7.4 Hz), 0.84-0.76 (1H, m), 0.98-0.94 (1H, m), 1.32-1.23 (2H, m), 1.74-1.68 (2H, m), 2.12 (2H, t, J = 6.6 Hz), 2.19 ( 3H, s), 2.34 (4H, t, J = 4.7 Hz), 3.01 (4H, t, J = 4.7 Hz), 6.77 (1H, dd, J = 2.4, 8.4 Hz), 6.83 (1H, d, J = 7.5 Hz), 6.87 (1H, d, J = 2.4 Hz), 6.96 (1H, dt, J = 0.7, 7.0 Hz), 7.17-7.10 (3H, m), 10.3 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 18.6, 22.0, 26.6, 30.5, 37.1, 48.2, 52.6, 53.3, 57.6, 109.2, 114.3, 115.3, 121.5, 123.1, 124.8, 127.6, 131.4, 132.4, 133.8, 142.7, 150.6, 181.0 ppm.

Anal for Formula C ₂₅ H ₃₂ ClN ₃ O (426.01):

Calc. For C 70,49, H 7.57, Cl 8.32, N 9.86%.

Found: C 70.18, H 7.54, Cl 8.33, N 9.79%.

Example 100

3- {4- [4- (3-Chloro-4-fluorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (3-chloro-4-fluoro-phenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 121-124 ° C. (hexane-ethyl acetate).

IR (KBr): 3441, 1713 (C = O), 752 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 0.95-0.88 (1H, m), 1.15-1.10 (1H, m), 1.47-1.35 (2H, m), 1.82-1.73 (2H, m), 1.97-1.88 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.49 (4H, t, J = 5.0 Hz), 3.06 (4H, t, J = 5.0 Hz), 6.72 (1H, ddd, J = 3.0, 3.9, 9.1 Hz), 6.88 (1H, dd, J = 2.9, 6.3 Hz), 6.88 (1H, d, J = 7,9 Hz), 7.00 (1H, t, J = 8.9 Hz), 7.05 (1H, dt, J = 1.0, 7.5 Hz), 7.12 (1H, dt, J = 0.7, 7.4 Hz), 7.21 (1H, dt, J = 1.5, 7.6 Hz), 7.88 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 50.3 and 101 MHz): 8.5, 22.2, 26.9, 31.1, 37.6, 49.5, 52.9, 54.1, 58.1, 109.3, 115.6 (d, J = 6.5 Hz), 116.5 (d, J = 21.7 Hz), 117.8, 120.9 (d, J = 18.4 Hz), 122.4, 123.1, 127.6, 132.6, 141.1, 148.4 (d, J = 2.7 Hz), 152.1 (d, J = 241.1 Hz), 181.9 ppm .

Anal for Formula C ₂₄ H ₂₉ ClFN ₃ O (429.97):

Calc. For C 67.04, H 6.80, Cl 8.25, N 9.77%.

Found: C 66.62, H 6.78, Cl 8.26, N 9.61%.

Example 101

3- {4- [4- (5-chloro-2-methoxyphenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one mono Hydrochloride

Treatment of the title compound starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (5-chloro-2-methoxyphenyl) -piperazine Prepared according to Method H by applying Method 2.

M.p .: 259-263 ° C.

IR (KBr): 3141 (NH), 2448 (HCl), 1704 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.87-0.76 (1H, m), 1.00-0.92 (1H, m), 1.81-1.60 ( 6H, m), 3.11-2.94 (6H, m), 3.49-3.40 (4H, m), 3.78 (3H, s), 6.87 (1H, d, J = 7.7 Hz), 6.90 (1H, d, J = 2.5 Hz), 7.02-6.96 (2H, m), 7.04 (1H, dd, J = 2.4, 8.7 Hz), 7.18 (1H, dt, J = 1.0, 7.7 Hz), 7.22 (1H, d, J = 7.3 Hz), 10.44 (1H, s), 11.36 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 21.4, 23.2, 30.3, 36.6, 46.6, 50.9, 53.2, 55.1, 55.9, 109.3, 113.4, 118.3, 121.7, 122.6, 123.2, 124.6, 127.8, 132.1, 140.8, 142.7, 150.8, 180.7 ppm.

Anal for Formula C ₂₅ H ₃₃ Cl ₂ N ₃ 0 ₂ (478.47):

Calc. For C 62.76, H 6.95, Cl 14.82, N 8.78%.

Found: C 62.39, H 7.02, Cl 14.75, N 8.62%.

Example 102

3- (4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-isobutyl-7-methyl-1,3-dihydro-2H indol-2-one monohydro Chloride

The title compound is derived from 3- (4-chlorobutyl) -3-isobutyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Treatment Method 2 was applied to prepare according to Method H.

M.p .: 146-149 ° C.

IR (KBr): 3390, 3167, 1706 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.57 (3H, d, J = 6.7 Hz), 0.67 (3H, d, J = 6.7 Hz), 0.82-0.70 (1H, m), 1.02 -0.88 (1H, m), 1.28-1.18 (1H, m), 1.76-1.57 (6H, m), 2.21 (3H, s), 3.13-2.90 (6H, m), 3.44-3.42 (2H, m) , 3.75-3.73 (2H, m), 6.90 (1H, t, J = 7.4 Hz), 6.99 (2H, d, J = 9.2 Hz), 7.27 (2H, d, J = 9.2 Hz), 10.44 (1H, s), 11.0 (1H, broad singlet) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 16.7, 20.9, 23.2, 23.3, 24.3, 25.0, 38.9, 45.3, 45.9, 50.4, 52.3, 55.1, 117.6, 118.6, 120.8, 121.5, 123.7, 128.9, 129.0, 132.1, 141.0, 148.6, 181.7 ppm.

Anal for Formula C ₂₇ H ₃₇ Cl ₂ N ₃ 0 (490.52):

Calc. For C 66.11, H 7.60, Cl 14.46, N 8.57%.

Found: C 65.94, H 7.54, Cl 14.25, N 8.47%.

Example 103

3- {4- [4- (2,4-Dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monohydrochloride

Treatment of the title compound starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (2,4-dichloro-phenyl) -piperazine 2 was applied to prepare according to Method H.

M.p .: 146-148 ° C.

IR (KBr): 3157, 1717 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.86-0.78 (1H, m), 1.00-0.94 (1H, m), 1.81-1.61 ( 6H, m), 3.46-2.97 (10H, m), 6.87 (1H, d, J = 7.6 Hz), 7.00 (1H, dt, J = 0.9, 7.5 Hz), 7.18 (1H, dt, J = 1.3, 7.6 Hz), 7.21 (1H, d, J = 8.7 Hz), 7.22 (1H, d, J = 6.8 Hz), 7.39 (1H, dd, J = 2.5, 8.7 Hz), 7.58 (1H, d, J = 2.5 Hz), 10.45 (1 H, s), 11.20 (1 H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 21.4, 23.3, 30.3, 36.6, 47.6, 51.0, 53.2, 55.2, 109.4, 121.7, 122.5, 123.2, 127.8, 128,1, 128.3, 128.6, 129.9, 132.1, 142.7, 146.7, 180.8 ppm.

Anal for Formula C ₂₄ H ₃₀ Cl ₃ N ₃ O (482.89):

Calc. For C 59.70, H 6.26, Cl 22.03, N 8.70%.

Found: C 59.52, H 6.29, Cl 21.32, N 8.39%.

Example 104

3- {4- [4- (3-Chlorophenyl) -piperazin-1-yl] -butyl) -3-isobutyl-7-methyl-1,3-dihydro-2H-indol-2-one mono Hydrochloride

The title compound is derived from 3- (4-chlorobutyl) -3-isobutyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) -piperazine Treatment Method 2 was applied to prepare according to Method H.

M.p .: 125-128 ° C.

IR (KBr): 3386, 3160, 1711 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.52 (1H, d, J = 6.7 Hz), 0.63 (1H, d, J = 6.6 Hz), 0.91-0.87 (1H, m), 0.75 -0.67 (1H, m), 1.21-1.13 (1H, m), 1.74-1.55 (6H, m), 2.18 (3H, s), 2.91-2.89 (4H, m), 3.14 (2H, m), 3.44 -3.23 (2H, m), 3.76 (2H, m), 6.99-6.80 (6H, m), 7.21 (1H, t, J = 8.2 Hz), 10.43 (1H, s), 11.12 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 16.7, 20.9, 23.2, 23.3, 24.3, 25.0, 44.9, 45.9, 50.3, 52.3, 55.1, 56.2, 114.3, 115.4, 118.6, 119.3, 120.8, 121.6, 129.1, 130.8, 132.1, 134.1, 141.0, 151.0, 181.7 ppm.

Anal for Formula C ₂₇ H ₃₇ Cl ₂ N ₃ 0 (490.52):

Calc. For C 66.11, H 7.60, Cl 14.46, N 8.57%.

Found: C 63.33, H 7.95, Cl 13.66, N 8.22%.

Example 105

3-ethyl-3- {4- [4- {3-fluorophenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one monohydro-chloride

Treatment method 2 starting from 3- (4-chlorobutyl) -3-ethyl-1,3-di-hydro-2H-indol-2-one and 1- (3-fluorophenyl) -piperazine Was prepared according to Method H.

Mp : 181-183 ° C.

IR (KBr): 3168, 1705 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.83-0.77 (1H, m), 0.99-0.94 (1H, m), 1.81-1.61 ( 6H, m), 3.04-2.95 (4H, m), 3.20 (2H, t, J = 11.9 Hz), 3.46-3.41 (2H, m), 3.82 (2H, d, J = 13.1 Hz), 6.62 (1H , dt, J = 1.9, 8.4 Hz), 6.85-6.81 (2H, m), 6.88 (1H, d, J = 7.7 Hz), 7.00 (1H, dt, J = 0.9, 7.5 Hz), 7.29-7.16 ( 3H, m), 10.5 (1H, s), 11.2 (1H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.6, 21.5, 23.2, 30.3, 36.6, 44.9, 50.3, 53.2, 55.1, 102.7 (d, 1 = 25.6 Hz), 106.0 (d, J = 21.4 Hz), 109.4, 111.5 (d, J = 1.9 Hz), 121.7, 123.2, 127.8, 130.8 (d, J = 9.9 Hz), 132.1, 142.7, 151.5 (d, J = 9.9 Hz), 163.4 (d, J = 241.1 Hz), 180.8 ppm.

Anal for Formula C ₂₄ H ₃₁ ClFN ₃ O (431.99):

Calc. For C 66.73, H 7.23, Cl 8.21, N 9.73%.

Found: C 66.14, H 7.21, Cl 8.09, N 9.60%.

Example 106

5,7-dichloro-3-ethyl-3- {4- [4- (4-fluorophenyl) -piperazin-1-yl] -butyl) -1,3-dihydro-2H-indole-2- Monohydrochloride

The title compound was obtained from 5,7-dichloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 4- (4-fluoro-phenyl) -piperazine. Prepared according to Method H by starting Treatment Method 1.

M.p .: 227-229 ° C.

IR (KBr): 3177, 2510, 2447, 1726, 1711 (C = O), cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.52 (3H, t), 0.82-0.80 (1H, m), 0.96-0.94 (1H, m), 1.89-1.64 (6H, m), 3.14-2.98 (6H, m), 3.45 (2H, m), 3.67 (2H, d, J = 12.1 Hz), 7.00 (2H, dd, J = 4.7, 9.5 Hz), 7.09 (2H, t, J = 8.9 Hz), 7.43 (2H, s), 11.04 (2H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.5, 21.4, 23.2, 30.3, 36.4, 46.2, 50.6, 54.9, 114.3, 115.6 (d, J = 22.1 Hz), 118.0 (d, J = 7.6 Hz), 122.6, 126.5, 127.4, 135.8, 139.5, 146.6 (d, J = 1.9 Hz), 156.7 (d, J = 236.9 Hz), 180.4 Hz) ppm.

Anal for Formula C ₂₄ H ₂₉ Cl ₃ FN ₃ 0 (500.88):

Calc. For C 57.55, H 5.84, Cl 21.23, N 8.39%.

Found: C 57.03, H 5.97, Cl 20.71, N 8.22%.

Example 107

5-chloro-3- {4- [4- (2,4-dichlorophenyl) -piperazin-1-yl] butyl} -3-ethyl-6-fluoro-1,3-dihydro-2H-indole 2-one monohydrochloride

The title compound is referred to as 5-chloro-3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H indol-2-one and 1- (2,4-dichlorophenyl)- Prepared according to Method H by applying Treatment Method 2 starting from piperazine.

M.p .: 238-240 ° C.

IR (KBr): 3144, 2549, 2469, 1706 (C = 0) cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 0.51 (3H, t, J = 7.3 Hz), 0.84-0.80 (1H, m), 0.95-0.90 (1H, m), 1.86-1.61 ( 6H, m), 3.17-3.01 (6H, m), 3.38-3.33 (2H, m), 3.47 (2H, d, J = 8.7 Hz), 6.88 (1H, d, J = 9.4 Hz), 7.21 (1H , d, J = 8.7 Hz), 7.40 (1H, dd, J = 2.4, 8,7 Hz), 7.53 (1H, d, J = 7.4 Hz), 7.59 (1H, d, J = 2.4 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 8.5, 21.4, 23.3, 30.2, 36.4, 47.751.1, 53.4, 55.1, 99.0 (d, J = 26.3 Hz), 111.7 (d, J = 18.7 Hz), 122.5, 125.1, 128.1, 128.3, 128.7, 129.5, 130.0, 143.0 (d, J = 11.1 Hz), 146.7, 156.9 (d, J = 243.8 Hz), 180.6 ppm.

Anal for Formula C ₂₄ H ₂₈ Cl ₄ FN ₃ 0 (535.32):

Calc. For H 5.27, N 7.85%.

Found: H 5.42, N 7.26%.

Example 108

3- {3- [4- (3-chlorophenyl) -piperazin-1-yl] propyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

Apply Treatment Method 1 starting from 3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3-chlorophenyl) -piperazine. Was prepared according to Method H.

M.p .: 119-120 ° C. (hexane-ethyl acetate).

] R (KBr): 3434, 3171, 1716 (C = O), 749 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 0.64 (3H, t, J = 7.4 Hz), 1.17-1.04 (1H, m), 1.40-1.24 (1H, m), 1.86-1.76 (2H, m), 2.00-1.88 (2H, m), 2.26 (2H, t, J = 7.4 Hz), 2.42 (4H, t, J = 5.1 Hz), 3.10 (4H, t, J = 5.1 Hz) 6.71 (1H , dd, J = 1.7, 8.4 Hz), 6.76 (1H, dd, J = 1.1, 7.9 Hz), 6.81 (1H, t, J = 2.1 Hz), 6.91 (1H, d, J = 7.7 Hz), 7.05 (1H, dt, J = 1.1, 7.5 Hz), 7.12 (1H, d, J = 6.3 Hz), 7.12 (1H, t, J = 8.2 Hz), 7.20 (1H, dt, J = 1.4, 7.6 Hz) , 8.96 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 101 MHz): 182.6, 152.2, 141.4, 134.8, 132.5, 129.9, 127.7, 123.0, 122.4, 119.1, 115.6, 113.7, 109.6, 58.2, 54.0, 52.8, 48.5, 35.2, 31.0, 21.2, 8.6 ppm.

Anal for Formula C ₂₃ H ₂₈ ClN ₃ 0 (397.95):

Calc. For C 69.42, H 7.09, Cl 8.91, N 10.56%.

Found: C 69.28, H 7.06, Cl 8.82, N 10.38%.

Example 109

3- {6- [4- (3-chlorophenyl) -piperazin-1-yl] -hexyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monohydrochloride

The reaction mixture was prepared by starting from 3- (6-bromohexyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (3-chlorophenyl) -piperazine. Prepared by treatment in accordance with.

M.p .: 124-127 ° C.

IR (KBr): 3073, 1711 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 0.50 (3H, t, J = 7.3 Hz), 1.02-0.79 (2H, m), 1.31-1.13 (6H, m), 1.78-1.65 (4H, m), 2.20 (2H, t, J = 7.0 Hz), 2.40 (4H, t, J = 4.8 Hz), 3.12 (4H, t, J = 4.8 Hz), 7.02-6.73 (5H, m), 7.24-7.13 (3H, m), 10.33 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 50.3 MHz): 8.6, 23.9, 26.2, 26.7, 29.2, 30.4, 37.1, 47.8, 52.7, 53.3, 57.8, 109.2, 113.7, 114.6, 118.1, 121.6, 123.0, 127.6, 130.5, 132.5, 134.0, 142.7, 152.4, 181.0 ppm.

Anal for Formula C ₂₆ H ₃₄ ClN ₃ O (440.03):

Calc. For C 70.97, H 7.79, Cl 8.06, N 9.55%.

Found: C 71.20, H 7.56, Cl 7.86, N 9.35%.

Example 110

3-ethyl-3- [6- (4-pyridin-2-yl-piperazin-1-yl) -hexyl] -1,3-dihydro-2H-indol-2-one monooxalate

Treatment method 3 starting from 3- (6-bromohexyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 2- (pyridin-1-yl) -piperazine Was prepared according to Method H.

M.p .: 132-135 ° C.

l R (KBr): 3000-2400, 1702 (C = O) cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 0.50 (3H, t, J = 7.3 Hz), 0.96-0.80 (2H, m), 1.78-1.52 (4H, m), 2.89 (2H, t, J = 8.0 Hz), 3.11 (4H, m), 3.70 (4H, m), 6.72 (1H, dd, J = 5.1, 7.0 Hz), 7.02-6.81 (3H, m), 7.21-7.12 (2H , m), 7.59 (1H, dt, J = 2.1, 7.8 Hz), 8.15 (1H, dd, J = 1.3, 5.1 Hz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 50.3 MHz): 8.6, 23.4, 23.9, 26.1, 28.9, 30.5, 37.0, 42.2, 50.7, 53.3, 55.8, 107.8, 109.3, 114.3, 121.7, 123.1, 127.7, 132.5, 138.1, 142.7, 147.8, 158.3, 164.5, 181.0 ppm.

Elemental Analysis for Formula C ₂₇ H ₃₆ N ₄ 0 ₅ (496.61):

Calculated: C 65.30, H 7.31, N 11.28%.

Found: C 64.01, H 7.40, N 10.85%.

Example 111

3-ethyl-5-fluoro-3- {4- [4- (4-fluorophenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-fluorophenyl) piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 119-122 ° C.

IR (KBr): 3252, 1716 (C = O), 1178 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 500 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.94-0.89 (1H, m), 1.14-1.09 (1H, m), 1.48-1.37 (2H, m), 1.80-1.72 (2H, m), 1.96-1.89 (2H, m), 2.25 (2H, t, J = 7.7 Hz), 2.51 (4H, t, J = 4.9 Hz), 3.06 (4H, t , J = 4.9 Hz), 6.95-6.89 (3H, m), 6.87 (1H, dd, J = 2.4, 8.2 Hz), 6.86-6.81 (3H, m), 9.53 (1H, s) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 125.6 MHz): 8.4, 22.1, 26.8, 30.9, 37.4, 50.0, 53.0, 54.9 (d, J = 1.7 Hz), 58.0, 110.1 (d, J = 8.1 Hz), 110.8 (d, J = 23.9 Hz), 113.9 (d, J = 23.5 Hz), 115.4 (d, J = 22.2 Hz), 117.6 (d, J = 7.7 Hz), 134.4 (d, J = 7.7 Hz), 137.4 (d, J = 1.7 Hz), 147.9 (d, J = 2.1 Hz), 157.0 (d, J = 238.8 Hz), 159.1 (d, J = 240.1 Hz), 182.9 ppm.

Chemical Formula C ₂₄ H ₂₉ F ₂ N ₃ 0 Elemental Analysis for (413.52):

Calculated: C 69.71, H 7.07, N 10.16%.

Found: C 69.90, H 6.96, N 10.20%.

Example 112

3- {4- [4- (3,5-Dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one monohydrochloride

Treatment method 2 was carried out starting from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (3,5-dichlorophenyl) -piperazine. Application was made according to Method H.

M.p .: 219-220 ° C.

IR (KBr): 3205, 2396, 1722 (C = O), 798 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.81-0.77 (1H, m), 0.98-0.93 (1H, m), 1.80-1.61 ( 6H, m), 2.97-2.94 (4H, m), 3.27 (2H, t, J = 12.4 Hz), 3.46-3.38 (2H, m), 3.91 (2H, d, J = 13.2 Hz), 6,87 (1H, td, J = 0.5, 7.7 Hz), 6.94 (1H, t, J = 1.7 Hz), 7.00 (1H, dt, J = 1.0, 7.6 Hz), 7.03 (2H, d, J = 1.7 Hz) , 7.18 (1H, dt, J = 1.4, 7.7 Hz), 7.21 (lH, td, J = 0.6, 7.3 Hz), 10.46 (1H, s), 11.33 (1H, sz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 125.6 MHz): 8.6, 21.4, 23.2, 30.3, 36.6, 44.5, 50,1, 53.1, 55.0, 109.4, 113.8, 118.3, 121.7, 123.2, 127.7, 132.1, 134.9, 142.7, 151.4, 180.7 ppm.

Elemental Analysis for Formula C ₂₄ H ₃₀ Cl ₃ N ₃ 0 (482.89):

Calc. For C 59.70, H 6.26, Cl 22.03, N 8.70%.

Found: C 59.02, H 6.20, Cl 21.92, N 8.69%.

Example 113

3-ethyl-3- {4- {4- (4-fluorophenyl) -piperazin-1-yl) -butyl} -5-methyl-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1- (4-fluorophenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 146-149 ° C.

IR (KBr): 3170, 1715 (C = O), 1162 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.86-0.77 (1H, m), 1.00-0.94 (1H, m), 1.37-1.24 ( 2H, m), 1.76-1.68 (4H, m), 2.20-2.10 (2H, m), 2.26 (3H, s), 2.38 (4H, sz), 2.99 (4H, t, J = 4.9 Hz), 6.73 (1H, d, J = 7.8 Hz), 6.90 (2H, dd, J = 4.6, 9.3 Hz), 6.96 (1H, d, J = 7.8 Hz), 6.99 (1H, s), 7.02 (2H, t, J = 8.9 Hz), 10.24 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 125.3 MHz): 8.6, 21.0, 22.0, 26.5, 30.6, 37.1, 49.1, 52.8, 53.4, 57.6, 108.9, 115.3 (d, J = 22.0 Hz), 117.0 ( d, J = 7.3 Hz), 123.7, 127.9, 130.3, 132.5, 140.2, 148.1 (d, J = 2.0 Hz), 156.1 (d, J = 235.8 Hz), 181.0 ppm.

Chemical Formula C ₂₅ H ₃₂ FN ₃ O Elemental Analysis for (409.55):

Calc .: C 73.32, H 7.88, N 10.26%.

Found: C 73.10, H 7.81, N 10.12%.

Example 114

3- {4- [4- (3,5-Dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2- On

The title compound was obtained from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3,5-dichlorophenyl) -piperazine. Prepared according to Method H by starting Treatment Method 1.

M.p .: 122-124 ° C.

IR (KBr): 1719 (C = O), 986, 968, 822 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.81-0.77 (1H, m), 1.18-0.95 (1H, m), 1.34-1.27 ( 2H, m), 1.80-1.69 (4H, m), 2.18-2.13 (2H, m), 2.35 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 6.81 (1H , dd, J = 4.4, 8.4 Hz), 6.83 (1H, t, J = 1.7 Hz), 6.89 (2H, d, J = 1.7 Hz), 6.98 (1H, ddd, J = 2.7, 8.4, 9.6 Hz) , 7.15 (1H, doublet of doublets, J = 2.7, 8.4 Hz), 10.37 ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 125.6 MHz): 8.5, 21.9, 26.4, 30A, 36.9, 47.3, 52.4, 54.1 (d, J = 1.5 Hz), 57.4, 109.8 (d, J = 8.3 Hz ), 111.1 (d, J = 23.9 Hz), 113.0, 113.8 (d, J = 23.4 Hz), 117.0, 134.5 (d, J = 7.8 Hz), 134.7, 138.8 (d, J = 1.5 Hz), 152.8, 158.3 (d, J = 236.3 Hz), 180.9 ppm.

Chemical Formula C ₂₄ H ₂₈ Cl ₂ FN ₃ O Elemental Analysis for (464.41):

Calc. For C 62.07, H 6.08, Cl 15.27, N 9.05%.

Found: C 61.84, H 5.86, Cl 14.97, N 8.94%.

Example 115

3- {4- [4- (3,4-Dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2- On

The title compound was obtained from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3,4-dichlorophenyl) -piperazine. Prepared according to Method H by starting Treatment Method 1.

M.p .: 152-155 ° C.

IR (KBr): 3058, 1709 (C = 0), 823, 794 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.82-0.76 (1H, m), 0.99-0.92 (1H, m), 1.35-1.24 ( 2H, m), 2.00-1.67 (4H, m), 2.19-2.11 (2H, m), 2.36 (4H, t, J = 5.0 Hz), 3.09 (4H, t, J = 5.0 Hz), 6.81 (1H, dd, J = 4.4, 8.4 Hz), 6.89 (1H, dd, J = 2.9 , 9.0 Hz), 6.98 (1H, ddd, J = 2.7, 8.4, 9.6 Hz), 7.08 (1H, d, J = 2.9 Hz), 7.15 (1H, dd, J = 2.7, 8.6 Hz), 7.36 (1H , d, J = 9.0 Hz), 10.36 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 125.6 MHz): 8.5, 21.9, 26.4, 30.4, 36.9, 47.6, 52.4, 54.1, 57.4, 109.8 (d, J = 8.3 Hz), 111.2 (d, J = 24.4 Hz), 113.8 (d, J = 23.4 Hz), 115.3, 116.2, 119.6, 130.6, 131.6, 134.5 (d, J = 8.3 Hz), 138.8, 150.9, 158.3 (d, J = 236.3 Hz), 180.9 ppm.

Elemental Analysis for Formula C ₂₄ H ₂₈ Cl ₂ FN ₃ 0 (464.41):

Calc. For C 62.07, H 6.08, Cl 15.27, N 9.05%.

Found: C 61.67, H 6.00, Cl 15.16, N 8.95%.

Example 116

3-ethyl-5-fluoro-3- [4- (4-phenyl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one

The title compound was subjected to Treatment Method 1 starting from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-phenylpiperazine Prepared according to Method H.

M.p .: 125-130 ° C.

IR (KBr): 3032, 1710 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.86-0.76 (1H, m), 1.04-0.94 (1H, m), 1.40-1.25 ( 2H, m), 1.80-1.69 (4H, m), 2.19-2.14 (2H, m), 2.39 (4H, s), 3.05 (4H, t, J = 4.7 Hz), 6.76 (1H, t, J = 7.3 Hz), 6.83 (1H, dd, J = 4.4, 8.4 Hz), 6.89 (2H, d, J = 8.2 Hz), 6.99 (1H, dt, J = 2.7, 9.0 Hz), 7.15 (1H, dd, J = 2.6, 8.4 Hz), 7.19 (2H, t, J = 7.5 Hz), 10.39 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 125.6 MHz): 8.5, 22.0, 26.4, 30.4, 36.9, 48.3, 52.8, 54.1 (d, J = 2.0 Hz), 57.5, 109.8 (d, J = 8.3 Hz ), 111.1 (d, J = 23.9 Hz), 113.8 (d, J = 23.0 Hz), 115.4, 118.9, 129.0, 134.5 (d, J = 7.8 Hz), 138.8 (d, J = 1.5 Hz), 151.2, 158.3 (d, J = 236.3 Hz), 180.9 ppm.

Elemental Analysis for Formula C ₂₄ H ₃₀ FN ₃ 0 (395.52):

Calc .: C 72.88, H 7.65, N 10.62%.

Found: C 71.88, H 7.71, N 10.71%.

Example 117

3- {4- [4- (3-Chloro-4-fluorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-6-fluoro-1,3-dihydro-2H-indole 2-one monohydrochloride

The title compound was prepared as 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-chloro-4-fluorophenyl)- Prepared according to Method H by applying Treatment Method 2 starting from piperazine.

M.p .: 94-96 ° C.

IR (KBr): 3422, 3159, 2877, 1715, 1504 (C = 0) cm ⁻¹ .

¹ H-NMR (CDCl ₃ , TMS, 500 MHz): 0.60 (3H, t, J = 7.4 Hz), 1.08-0.91 (2H, m), 1.93-1.69 (6H, m), 3.03-2.85 (4H, m), 3.5 (6H, sz), 7.07-6.70 (6H, m), 9.5 (1H, s), 12.2 (1H, sz) ppm.

¹³ C-NMR (CDCl ₃ , TMS, 125.6 MHz): 8.4, 21.7, 23.4, 31.1, 36.6, 47.2, 51.7, 53.4, 56.9, 98.7 (d, J = 26.9 Hz), 108.6 (d, J = 22.5 Hz ), 117.1, 119.8, 121.3 (d, J = 18.5 Hz), 123.7 (d, J = 9.8 Hz), 127.0 (d, J = 2.9 Hz), 142.9 (d, J. = 10.3 Hz), 146.5 (d, J = 2.9 Hz), 152.4, 154.4, 161.6, 163.5, 182.1 ppm.

Elemental Analysis for Formula C ₂₄ H ₂₉ Cl ₂ F ₂ N ₃ 0 (484.42):

Calc. For C 59.51, H 6.03, Cl 14.64, N 8.67%.

Found: C 58.84, H 6.15, Cl 14.26, N 8.57%.

Example 118

3-ethyl-6-fluoro-3- {4- [4- (4-fluorophenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one Monohydrochloride

Title compound starts from 3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-fluorophenyl) -piperazine Was prepared according to Method H by applying Treatment Method 2.

M.p .: 198-202 ° C.

IR (KBr): 2454, 1715 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 0.51 (3H, t, J-7.4 Hz), 0.96-0.79 (2H, m), 1.75-1.65 (6H, m), 3.44-2.93 ( 10H, m), 7.28-6.67 (7H, m), 10.6 (1H, s), 11.1 (1H, sz) ppm.

Elemental Analysis for Formula C ₂₄ H ₃₀ ClF ₂ N ₃ 0 (449.98):

Calc. For C 64.06, H 6.72, Cl 7.88, N 9.34%.

Found: C 63.63, H 6.87, Cl 7.50, N 8.94%.

Example 119

7-chloro-3-ethyl-5-fluoro-3- {4- [4- (4-fluorophenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indole 2-on

The title compound was purified by 7-chloro-3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-fluorophenyl)- Prepared according to Method H by applying Treatment Method 1 starting from piperazine.

M.p .: 161-162 ° C.

IR (KBr): 2956, 2786, 1721 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 0.52 (3H, t, J = 7.6 Hz), 0.99-0.75 (2H, m), 1.33-1.27 (2H, m), 1.86-1.68 ( 4H, m), 2.20-2.14 (2H, m), 2.41-2.36 (4H, m), 3.01-2.97 (4H, m), 7.07-6.87 (4H, m), 7.23 (2H, d, J = 8.8 Hz), 10.9 (1H, sz) ppm.

Elemental Analysis for Formula C ₂₄ H ₂₈ ClF ₂ N ₃ 0 (447.96):

Calc. For C 64.35, H 6.30, Cl 7.91, N 9.38%.

Found: C 64.22, H 6.40, Cl 8.06, N 9.09%.

Example 120

7-chloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indole- 2-one monohydrochloride

The title compound was diluted with 7-chloro-3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H indol-2-one and 1- (4-chlorophenyl) -piperazine. Prepared according to Method H by applying Treatment Method 2 starting from.

M.p .: 117-119 ° C.

IR (KBr): 3428, 1719 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.52 (3H, t, J = 7.4 Hz), 0.96-0.80 (2H, m), 1.86-1.64 (6H, m), 3.04-2.96 (2H, m), 3.20-3.15 (2H, m), 3.77-3.75 (2H, m), 3.91 (4H, m ), 7.30-6.99 (6H, m), 10.9 (1H, s), 11.3 (1H, sz) ppm.

Chemical Formula C ₂₄ H ₂₉ Cl ₃ FN ₃ 0 Elemental Analysis for (500.88):

Calc. For C 57.55, H 5.84, Cl 21.23, N 8.39%.

Found: C 56.31, H 5.94, Cl 21.81, N 8.06%.

Example 121

5-Chloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-indol-2-one

Treatment of the title compound starting from 5-chloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Prepared according to Method H by applying Method 1.

M.p .: 186-188 ° C.

IR (KBr): 3286, 2934, 1715 (C = 0), 1694 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 200 MHz): 0.64 (3H, t, J = 7.3 Hz), 1.11-0.91 (2H, m), 1.43-1.37 (2H, m), 1.98-1.71 ( 4H, m), 2.28-2.21 (2H, m), 2.52-2.47 (4H, m), 3.13-3.08 (4H, m), 6.86-6.77 (3H, m), 7.27-7.09 (4H, m), 8.9 (1H, sz) ppm.

Elemental Analysis for Formula C ₂₄ H ₂₉ Cl ₂ N ₃ 0 (446.42):

Calc. For C 64.57, H 6.55, Cl 15.88, N 9.41%.

Found: C 64.86, H 6.59, Cl 15.59, N 9.39%.

Example 122

5-Chloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-6-fluoro-1,3-dihydro-2H-indole- 2-on

The title compound was purified by 5-chloro-3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -pipe. Prepared according to Method H by applying Treatment Method 2 starting from Razine.

M.p .: 194-197 ° C.

IR (KBr): 3283, 2934, 1717 (C = 0), 1692 cm ⁻¹ .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.50 (311, t, J = 7.6 Hz), 0.95-0.78 (2H, m), 1.33-1.26 (2H, m), 1.82-1.66 ( 4H, m), 2.19-2.14 (2H, m), 2.38 (4H, s), 3.05 (4H, s), 6.92-6.84 (3H, m), 7.21 (2H, m), 7.47 (1H, m) , 10.6 (1H, s) ppm.

Elemental Analysis for Formula C ₂₄ H ₂₈ Cl ₂ FN ₃ O (464.41):

Calc. For C 62.07, H 6.08, Cl 15.27, N 9.05%.

Found: C 61.94, H 6.24, Cl 14.62, N 8.64%.

Example 123

3- {5- [4- (4-Chlorophenyl) -piperazin-1-yl] -pentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound was subjected to Treatment Method 1 starting from 3- (5-chloropentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1 (4-chlorophenyl) -piperazine. Prepared according to Method H.

M.p .: 142-143 ° C.,

IR (KBr): 2939, 1700 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.50 (3H, t, J = 7.6 Hz), 0.97-0.78 (2H, m), 1.14 (2H, m), 1.30 (2H, m) , 1.70 (4H, m), 2.16 (2H, m), 2.39 (4H, m), 3.06 (4H, m), 7.22-6.82 (8H, m), 10.3 (1H, s) ppm.

Elemental Analysis for Formula C ₂₅ H ₃₂ ClN ₃ 0 (426.01):

Calc. For C 70,49, H 7.57, Cl 8.32, N 9.86%.

Found: C 70.23, H 7.50, Cl 8.13, N 9.99%.

Example 124

5,7-dichloro-3- {4- [4- (3,4-dichlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indole-2 -On

The title compound was converted into 5,7-dichloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (3,4-dichlorophenyl) -piperazine. Prepared according to Method H by applying Treatment Method 1 starting from.

M.p .: 164-165 ° C.

IR (KBr): 2969, 1734 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.98-0.78 (2H, m), 1.36-1.26 (2H, m), 1.84-1.70 ( 4H, m), 2.20-2.14 (2H, m), 2.36 (4H, sz), 3.10 (4H, m), 6.88 (1H, m), 7.08 (1H, s), 7.38-7.36 (2H, m) , 7.40 (1 H, s), 11.0 (1 H, s) ppm.

Elemental Analysis for Formula C ₂₄ H ₂₇ Cl ₄ N ₃ 0 (515.31):

Calc. For C 55.94, H 5.28, Cl 27.52, N 8.15%.

Found: C 56.35, H 5.18, Cl 27.12, N 8.10%.

Example 125

5,7-dichloro-3- {5- [4- (4-chlorophenyl) -piperazin-1-yl] -pentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound starts from 5,7-dichloro-3- (5-chloropentyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 145-148 ° C.

IR (KBr): 2963, 1723 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.51 (3H, t, J = 7.3 Hz), 0.98-0.77 (2H, m), 1.15 (2H, m), 1.32 (2H, m) , 1.85-1.68 (4H, m), 2.17 (2H, m), 2.40 (4H, sz), 3.06 (4H, sz), 6.92 (2H, m), 7.21 (2H, m), 7.38 (2H, m ), 10.99 (1H, s) ppm.

Elemental Analysis for Formula C ₂₅ H ₃₀ Cl ₃ N ₃ 0 (494.90):

Calc. For C 60.68, H 6.11, Cl 21.49, N 8.49%.

Found: C 60.59, H 6.20, Cl 21.14, N 8.51%.

Example 126

3- {4- [4- (2-Chloro-4-fluorophenyl) -piperazin-1-yl) -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one

The title compound is derived from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (2-chloro-4-fluorophenyl) -piperazine Treatment Method 1 was applied to prepare according to Method H.

M.p .: 125-126 ° C.

IR (KBr): 3168, 2877, 1713 (C = O), 1507 cm ^-1 .

¹ H-NMR (CDCl ₃ , TMS, 500 MHz): 0.63 (3H, t, J = 7.4 Hz), 0.93-0.88 (1H, m), 1.13-1.09 (1H, m), 1.46-1.35 (2H, m), 1.81-1.75 (2H, m), 1.96-1.89 (2H, m), 2.25-2.21 (2H, m), 2.48 (4H, sz), 3.05 (4H, sz), 6.71 (1H, m) , 6.86 (1H, m), 6.92 (1H, m), 6.97 (1H, m), 7.05 (1H, m), 7.11 (1H, m), 7.20 (1H, m), 9.02 (1H, s) ppm.

Elemental Analysis for Formula C ₂₄ H ₂₉ ClFN ₃ 0 (429.97):

Calc. For C 67.04, H 6.80, Cl 8.25, N 9.77%.

Found; C 67.47, H 6.85, Cl 8.17, N 9.58%.

Example 127

3-ethyl-3- {4- [4- (4-fluoro-2-methylphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one monohydro Chloride

Treatment of the title compound from the starting compound 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H indol-2-one and 1- (4-fluoro-2-methylphenyl) -piperazine 2 was applied to prepare according to Method H.

M.p .: 103-107 ° C.

IR (KBr): 3424, 1499, 1321 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.49 (3H, t, J = 7.3 Hz), 0.83-0.75 (1H, m), 0.98-0.91 (1H, m), 1.79-1.59 ( 6H, m), 2.22 (3H, s), 3.05 (6H, sz), 3.35 (4H, sz), 6.84 (1H, m), 6.98 (2H, m), 7.02 (2H, m), 7.16 (1H , m), 7.19 (1H, m), 10.4 (1H, s), 11.1 (1H, sz) ppm.

Elemental Analysis for Formula C ₂₅ H ₃₃ ClFN ₃ 0 (446.01):

Calc. For C 67.33, H 7.46, Cl 7.95, N 9.42%.

Found: C 66.31, H 7.68, Cl 7.72, N 9.15%.

Example 128

5,7-dichloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-methyl-1,3-dihydro-2H-indol-2-one

Title compound starts from 5,7-dichloro-3- (4-chlorobutyl) -3-methyl-1,3-dihydro-2H-indol-2-one and 1- (4-chlorophenyl) -piperazine Was prepared according to Method H by applying Treatment Method 1.

M.p .: 168-170 ° C.

IR (KBr): 296, 1731 (C = O), 1497 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 500 MHz): 0.85-0.78 (1H, m), 0.99-0.91 (1H, m), 1.27 (3H, s), 1.33 (2H, m), 1.85- 1.71 (2H, m), 2.22-2.13 (2H, m), 2.38 (4H, sz), 3.05 (4H, sz), 6.90 (2H, d, J = 8.9 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.40 (2H, m), 10.96 (1H, s) ppm.

Elemental Analysis for Formula C ₂₃ H ₂₆ Cl ₃ N ₃ 0 (466.84):

Calc. For C 59.18, H 5.61, Cl 22.78, N 9.00%.

Found: C 58.97, H 5.77, Cl 22.65, N 8.74%.

Claims (21)

A 3,3-dialkyl indol-2-one derivative of formula (I) or a pharmaceutically acceptable acid addition salt thereof:

Wherein R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s); R ² is hydrogen or halogen; R ³ is hydrogen, alkyl with 1 to 7 carbon atom (s) with or without aryl substituents or aryl with or without one or two halogen substituent (s); R ⁴ is alkyl having 1 to 7 carbon atom (s); R ⁵ is a group of formula (IIa) or (IIb),

Wherein Q and W are each nitrogen or CH; R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen, trifluoromethyl, alkyl or alkoxy having 1 to 7 carbon atom (s), or R ⁶ and R ⁷ together represent ethylenedioxy; m is 0, 1 or 2; a is a single, double or triple bond; n is 0, 1 or 2. R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s); R ² is hydrogen or halogen; R ³ is hydrogen; R ⁴ is ethyl or 2-methyl-propyl; R ⁵ is a group of formula (IIa) or (IIb), Wherein Q is nitrogen and W is CH; R ⁶ , R ⁷ and R ⁸ are each hydrogen, halogen or alkoxy having 1 to 7 carbon atom (s), or R ⁶ and R ⁷ together represent ethylenedioxy; m is 0 or 1; a is a single bond; n is 1, a 3,3-dialkyl indol-2-one derivative of formula (I) or a pharmaceutically acceptable acid addition salt thereof. The compound of claim 1, wherein 5-chloro-3- {3- [4- (3-chlorophenyl) -piperazin-1-yl] -propyl} -3-ethyl-1,3-dihydro-2H-indole 2-one, 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indole 2-one, 5,7-dichloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H- Indol-2-one, 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one , 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one , 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one-5sulfonamide , 3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-di Hydro-2H-indol-2-one, 3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl}- 3-isobutyl-1,3-dihydro-2H-indol-2-one, and 3-ethyl-3- {4- [4- (2-methoxyphenyl) -pipe -1-yl] -butyl} -1,3-dihydro -2H- indol-2-acceptable acid addition salts of the compound or a pharmaceutically thereof as medicaments that selected features from one. 5-chloro-3- {3- [4- (3-chlorophenyl) -piperazin-1-yl] -propyl} -3-ethyl-1,3-dihydro-2H-indol-2-one or its Pharmaceutically acceptable acid addition salts. 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one or Pharmaceutically acceptable acid addition salts thereof. 5,7-dichloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one Or a pharmaceutically acceptable acid addition salt thereof. 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable thereof Acid addition salts. 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one or Pharmaceutically acceptable acid addition salts thereof. 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro-2H-indol-2-one-5-sulfonamide or Pharmaceutically acceptable acid addition salts thereof. 3- {4- [4- (2,3-Dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] butyl} -3-ethyl-1,3-dihydro- 2H-indole-2-one or a pharmaceutically acceptable acid addition salt thereof. 3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] butyl} -3-isobutyl-1,3-dihydro -2H-indole-2-one or a pharmaceutically acceptable acid addition salt thereof. 3-ethyl-3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutically thereof Acceptable acid addition salts. As active ingredient one or more compounds of formula (I) according to any one of claims 1 to 12 or pharmaceutically acceptable acid addition salts thereof, together with one or more conventional carrier (s) or adjuvant (s) Pharmaceutical composition comprising. The method according to claim 13, wherein the central nervous system disorders, in particular anxiety, schizophrenia, mood disorders, social phobia, manic, mental decline, stroke, dementia, cell destruction in certain parts of the central nervous system, Alzheimer's disease, stress disorders, gastrointestinal diseases, Pharmaceutical composition, characterized in that it is suitable for treating or preventing cardiovascular disease, renal insufficiency, tinnitus or hearing loss. 15. The compound according to claim 13 or 14, wherein 5-chloro-3- {3- [4- (3-chlorophenyl) -piperazin-1-yl] -propyl} -3-ethyl-1,3 as active ingredient -Dihydro-2H-indol-2-one, 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3 -Dihydro-2H-indol-2-one, 5,7-dichloro-3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1, 3-dihydro-2H-indol-2-one, 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-1,3-dihydro- 2H-indol-2-one, 3- {4- [4- (4-chlorophenyl) -piperazin-1-yl] -butyl} -3-ethyl-5-fluoro-1,3-dihydro- 2H-indol-2-one, 3- {4- [4- (3-chlorophenyl) -piperazin-1-yl] -butyl) -3-ethyl-1,3-dihydro-2H-indole-2 -One-5-sulfonamide, 3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl} -3- Ethyl-1,3-dihydro-2H-indol-2-one, 3- {4- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazine-1 -Yl] -butyl) -3-isobutyl-1,3-dihydro-2H-indol-2-one, 3-ethyl -3- {4- [4- (2-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable acid thereof A pharmaceutical composition comprising an addition salt together with one or more conventional carrier (s) or adjuvant (s). (a) reacting a compound of formula (III) with a piperazine derivative of formula (IV) in the presence of an acid binder, (b) reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a strong base, or (c) To prepare a compound of formula (I) wherein n is 1 and a is a triple bond, the compound of formula (VIII) is reacted with formaldehyde, and thus the compound of formula (III) wherein L is a hydroxy group Is optionally converted to a compound of formula (III) wherein L is a halogen atom or an arylsulfonyloxy or alkylsulfonyloxy group, and thus a compound of formula (III) wherein a is a triple bond and n is 1 is in the presence of a strong base React with a compound of formula (IV) (d) to prepare a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as mentioned above and a is a single or double bond, a is a triple bond Reducing the corresponding compound of formula (I) (e) To prepare a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as mentioned above and a is a single bond, a is a double or triple bond Reducing the corresponding compound of formula (I) If desired, a first product, including halogenating a product containing hydrogen at the position of R ² , releasing the free base from its salt or converting it to an acid addition salt with a pharmaceutically acceptable organic or inorganic acid, Method for preparing a compound as defined in the claims:

Wherein L is a leaving group, m and n are each 0, 1 or 2, a is a single, double or triple bond, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as mentioned above. Use for the preparation of a medicament of a compound of formula (I) according to any of the preceding claims. 13. Mixing the at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 12 with a pharmaceutical carrier and optionally other auxiliaries to bring the mixture into the form of a herbal Including, central nervous system diseases, especially depression, anxiety, schizophrenia, mood disorders, social phobia, manic, mental decline, stroke, dementia, Alzheimer's disease, stress disorders, gastrointestinal diseases, cardiovascular disease, kidney failure, tinnitus or hearing loss A method of making a pharmaceutical composition suitable for treating or preventing. Central nervous system diseases, in particular depression, anxiety, schizophrenia, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition containing at least one compound of formula (I) or a pharmaceutically acceptable organic or inorganic acid addition salt thereof To treat or prevent mood disorders, social phobias, manic disorders, mental decline, stroke, dementia, cell death in certain areas of the central nervous system, Alzheimer's disease, stress disorders, gastrointestinal disease, cardiovascular disease, kidney failure, tinnitus or hearing loss Way. R ¹ is hydrogen, halogen, alkyl or sulfonamido with 1 to 7 carbon atom (s); R ² is hydrogen or halogen; R ³ is hydrogen, alkyl with 1 to 7 carbon atom (s) with or without aryl substituents or aryl with or without one or two halogen substituent (s); R ⁴ is alkyl having 1 to 7 carbon atom (s); L is leaving group m and n are 0, 1 or 2, A compound of formula (III) or an acid addition salt thereof, wherein a is a single, double or triple bond. A process for preparing a compound of formula (III), wherein the substituent is as defined in claim 20, comprising reacting a compound of formula (V) with a compound of formula (VI) in the presence of a strong base.

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